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TABLE OF CONTENTS Volume 5, Number 1, Jan-Mar 2001 Previous Issue / Next Issue

Genes GRAF (GTPase activating protein for Rho associated with FAK) (5q31). Stig Bojesen, Arndt Borkhardt. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 1-4. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/GRAFID291.html

HMGIY (High mobility group protein (non histone chromosomal) isoform I and Y) (6p21.3). Gilka J.F. Gattas, Florence Pedeutour. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 5-14. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/HMGIYID221.html

PU.1 (11p11-22). Françoise Moreau-Gachelin. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 15-19. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/SPI1ID269.html

FGFR1 (Fibroblast Growth Factor Receptor 1) (8p12) - updated. Marie-Josèphe Pébusque. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 20-27. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/FGFR1113.html

MLL (myeloid/lymphoid or mixed lineage leukemia) (11q23) - updated. Jay L Hess, Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 28-38. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/MLL.html

PRDX1 (peroxiredoxin 1) (1p34.1) - updated. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 39-44. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (5) I

URL : http://AtlasGeneticsOncology.org/Genes/PAGID266.html

PTCH1 (9q22.3) - updated. Erika Lindström, Rune Toftgård. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 45-53. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/PTCH100.html

TFF2 (TreFoil Factor 2) (21q22.3). Catherine Tomasetto. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 54-58. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/TFF2ID264.html

FGFR1OP (FGFR1 oncogene partner) (6q27). Marie-Joséphe Pébusque. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 59-63. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/FOPID140.html

MST1R (Macrophage stimulating 1 receptor) (3p21.31). Debora Angeloni, Michael I. Lerman. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 64-73. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/RONID287.html

FIM (fused in myeloproliferative disorders) (13q12) - updated. Marie-Joséphe Pébusque. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 74-79. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Genes/ZNF198ID114.html

Leukaemias t(1;3)(p36;q21) - updated. Pascale Cornillet-Lefebvre, Sylvie Daliphard, Stéphanie Struski. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 80-83. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t0103.html

del(17p) in non-Hodgkin's lymphoma (NHL). Antonio Cuneo, Gianluigi Castoldi. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 84-86. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/del17pNHLID2083.html

del(20q) in myeloid malignancies. Chrystèle Bilhou-Nabera. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 87-89. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/del20qID1040.html

Juvenile Chronic Myelogenous Leukemia (JCML). Jay L. Hess. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 90-93. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (5) II

URL : http://AtlasGeneticsOncology.org/Anomalies/JCMLID1099.html

t(6;8)(q27;p12). Marie-Josèphe Pébusque. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 94-96. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t68ID1090.html

t(8;13)(p12;q12) - updated. Marie-Josèphe Pébusque, and Nick CP Cross. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 97-100. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t813ID1094.html

t(9;12)(q34;p13). Nyla A. Heerema. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 101-103. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t912ID1080.html

11q23 rearrangements in leukaemia - updated. Jean-Loup Huret. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 104-114. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/11q23ID1030.html

del(11q) in non-Hodgkin's lymphoma (NHL). Antonio Cuneo, Gianluigi Castoldi. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 115-117. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/del11qNHLID2020.html

del(7q) in non-Hodgkin's lymphoma (NHL). Antonio Cuneo, Gianluigi Castoldi. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 118-119. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/del7qNHLID2082.html

t(1;14)(p22;q32) in non Hodgkin's lymphoma (NHL). Antonio Cuneo, Gianluigi Castoldi. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 120-121. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t114ID2044.html

t(5;10)(q33;q21)E. Cristina Mecucci. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 122-123. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/t510ID1166.html

+3 or trisomy 3 in non Hodgkin's lymphoma (NHL). Antonio Cuneo, Gianluigi Castoldi. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 124-126. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/tri3NHLID2008.html

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (5) III

Y loss in leukemia. Daniel L. Van Dyke. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 127-130. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Anomalies/YlossID1089.html

Solid Tumours Nervous system: Astrocytic tumors. Anne Marie Capodano. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 131-138. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Tumors/AstrocytID5007.html

Cancer Prone Diseases Beckwith-Wiedemann syndrome. Marcel Mannens. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 139-144. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/BeckwithWiedemannID10037.html

Hereditary breast cancer. Kaija Holli. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 146-151. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/HeredBreastCanID10062.html

Variegated aneuploidy related to premature centromere division (PCD). Alberto Plaja. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 152-156. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/VariegAneuplPCDID10069.html

Hereditary Pancreatic Cancer. Ralph H. Hruban, Scott E. Kern. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 157-164. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/HeredPancrCanID10068.html

Li-Fraumeni Syndrome. Jenny M Varley. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 165-168. [Full Text] [PDF] URL : http://AtlasGeneticsOncology.org/Kprones/LiFraumeniID10011.html

Deep InsightsCase ReportsEducational Items © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2001; 5 (5) IV

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Atlas Genet Cytogenet Oncol Haematol 2001; 5 (5) V


GRAF (GTPase activating protein for Rho associated with FAK)

IdentityOther names KIAA0621

OPHN1L Location 5q31 just centromeric of GRL

DNA/RNADescription at least 24 exons Transcription two isoforms of 2277 bp (leukocytes) and 2442 bp (brain); transcripts of

4,4 and 9,5 kb

Protein

Description isoform A: 759 amino acids, 86 kDa; isoform B: 814 amino acids. 92

kDa Expression highly expressed in epithelial tissues i.e. pancreas islet beta-cells,

testicles, prostate, mammary gland, GI glands, squamous layer of skin epithelium; highly expressed in nervous tissues including enteric ganglia; expressed in cardiomyocytes, erythropoiesis cells and liver

Atlas Genet Cytogenet Oncol Haematol 2001; 1 -1-

Localisation mainly cytoplasmatic Function interacts with FAK and RhoA both in vivo and in vitro; acts as GTPase

activating protein (GAP) for the active GTP-bound RhoA.; negative regulator of RhoA

Homology Oligophrenin-1, Beta-chimerin, BCR

MutationsGerminal not known Somatic � deletion of four bases (251-254, A in ATG=nt1)

� Insert 1158 GRAF-base 1144, 5' 1 TA GAG ACA GGA TTT CAT CAT GTT GGC CAG GTT GGT TTT GAA 42 TTC CTG ACC TCA AGT GAT CCA CCT GCC TCG GCC TCC CAA AGT 84 GGT GGG ATT TTG G 3' ......GRAF-base 1145 � Insert 1299 GRAF-base 1285, 5' 1 TC ATC GTT GTC ATA TAA ATC GGC GAG GTA ATA TTC CAT CAG 42 GTA GAC ATA CG 3' ...GRAF-base 1286.Predicted STOP codon underlined. � Insert 2002 GRAF-base 1988 5' 1 G GTT CAT GCG AGT TCA GCA AGC AGT TAC CAT GTC TAC GGC 41 ATG CCA GGA TAC TGT TGG GAA GGT AGT ATT CCG T 3' ...GRAF-base 1989

Implicated inEntity t(5;11)(q31;q23) / acute non lymphocytic leukemia --> MLL - GRAF Disease acute non lymphocytic leukemia and myelodysplastic syndrome with

del(5q) Prognosis unknown; only a few cases unknown Cytogenetics del(5q) Hybrid/Mutated Gene 5' MLL 3' GRAF

Abnormal Protein MLL-GRAF

Oncogenesis basically unknown; a bi-allelic loss of GRAF has been documented in three cases of ANLL

External links Nomenclature

GDB ARHGAP26 Entrez_Gene ARHGAP26 23092 Rho GTPase activating protein 26

Cards Atlas GRAFID291


GeneCards ARHGAP26 Ensembl ARHGAP26 CancerGene GRAF Genatlas ARHGAP26 GeneLynx ARHGAP26 eGenome ARHGAP26 euGene 23092

Genomic and cartography

GoldenPath ARHGAP26 - 5q31 chr5:142130476-142586243 + 5q31.3 (hg17-May_2004)

Ensembl ARHGAP26 - 5q31.3 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene ARHGAP26

Gene and transcription Genbank AF196313 [ SRS ] AF196313 [ ENTREZ ] Genbank AF508552 [ SRS ] AF508552 [ ENTREZ ] Genbank Y10388 [ SRS ] Y10388 [ ENTREZ ] Genbank AB014521 [ SRS ] AB014521 [ ENTREZ ] Genbank AK092488 [ SRS ] AK092488 [ ENTREZ ] RefSeq NM_015071 [ SRS ] NM_015071 [ ENTREZ ] RefSeq NT_086681 [ SRS ] NT_086681 [ ENTREZ ] AceView ARHGAP26 AceView - NCBI TRASER ARHGAP26 Traser - Stanford Unigene Hs.293593 [ SRS ] Hs.293593 [ NCBI ] HS293593 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt Q9UNA1 [ SRS] Q9UNA1 [ EXPASY ] Q9UNA1 [ INTERPRO ] CluSTr Q9UNA1 Blocks Q9UNA1

Polymorphism : SNP, mutations, diseases OMIM 605370 [ map ] GENECLINICS 605370 SNP ARHGAP26 [dbSNP-NCBI] SNP NM_015071 [SNP-NCI]

SNP ARHGAP26 [GeneSNPs - Utah] ARHGAP26 [SNP - CSHL] ARHGAP26] [HGBASE -

SRS] General knowledge

Family Browser ARHGAP26 [UCSC Family Browser]


SOURCE NM_015071 SMD Hs.293593 SAGE Hs.293593 Amigo function|Rho GTPase activator activity Amigo process|actin cytoskeleton organization and biogenesis Amigo component|cellular_component unknown Amigo process|neurogenesis PubGene ARHGAP26

Other databases Other database

HUGE: A Database of Human Unidentified Gene-Encoded Large Proteins

Probes PubMed

PubMed 7 Pubmed reference(s) in LocusLink

BibliographyThe human GRAF gene is fused to MLL in a unique t(5;11)(q31;q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute myeloid leukemia with a deletion 5q.Borkhardt A, Bojesen S, Haas OA, Fuchs U, Bartelheimer D, Loncarevic IF, Bohle RM, Harbott J, Repp R, Jaeger U, Viehmann S, Henn T, Korth P, Scharr D, Lampert F. Proc Natl Acad Sci U S A. 2000; 97: 9168-9173. Medline 20381355 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Contributor(s)Written 11-

2000 Stig Bojesen, Arndt Borkhardt

CitationThis paper should be referenced as such : Bojesen SE, Borkhardt A . GRAF (GTPase activating protein for Rho associated with FAK). Atlas Genet Cytogenet Oncol Haematol. November 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/GRAFID291.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



HMGIY (High mobility group protein (non histone chromosomal) isoform I and Y)

IdentityOther names HMG-I(Y), HMGI/Y

Hugo HMGIY Location 6p21.3 centromeric to HLA-A, telomeric to D6S19

DNA/RNA

Description 10 144 bp; 8 exons, 7 introns Transcription HMGI and HMGY are encoded by the same gene and are generated trough

alternative splicing; exons 1-4 are not transcribed, exons 5-7 encode three DNA binding domains; exon 5 contains a 33 bp segment subject to alternative splicing; exon 8 encodes the acidic carboxy-terminal end; RNA length: 1.85 kb.

Protein


Description 107 amino acids; three DNA binding domains (AT hooks) Expression expressed in embryonal cells; expressed in a variety of normal human

adult tissues such as heart, brain, lung, skeletal muscle, kidney, pancreas, spleen, thymus, testis, ovary, small intestine, submandibular gland and leukocytes; expressed in transformed cells with a malignant phenotype and in human malignant tumors such as prostate, thyroid carcinoma and colorectal carcinomas and a subset of benign lipomas.

Localisation nuclear Function � architectural transcription, non histone, factor that binds to the minor

groove of AT-rich DNA; alters DNA conformation by introducing bends and supercoils; HMGIY was shown to be an essential component of enhanceosome (higher order transcription enhancer complex); positive induction of several genes including IFN-b, E-selectin, interleukin-2 receptor a-chain, the chemokine MGSA/GRO, and the class II major histocompatibility complex gene HLA-DRA; negative regulation by binding the promoter regions of interleukin-4 and GP91-PHOX. � the precise function remains to be elucidated; probable role in regulation of chromatin structure and gene expression, and transcriptional regulation; potential oncogenic role

Homology member of the HMGI protein family, structural (but not expression pattern) homology with HMGIC

MutationsSomatic HMGIY is found involved in chromosome rearrangements in benign

tumours, mainly mesenchymal tumors

Implicated inEntity Pulmonary chondroid hamartoma Disease benign tumor of the lung Prognosis good Cytogenetics the most frequent rearrangement is a reciprocal balanced translocation t(6;14)

(p21.3; q24); the rearrangement between chromosomes 6 and 14 can sometimes be complex, identifiable by FISH; molecular results also suggest that the translocations might be more complex than shown by conventional cytogenetics, with the presence of additional cryptic rearrangements; translocations involving partner chromosomes other than chromosome 14, such as chromosomes 1, 3, 4, 5, 10, 12, 17 have also been reported; inversions inv(6)(p21q21) or


inv(6)(p21.3q26) have been described Hybrid/Mutated Gene

in most cases, the breakpoint was extragenic, located within a 80 kb region 3' of HMGIY; aberrant transcripts with truncation of sequences from the 3' UTR have been described; in only one case with inversion inv(6)(p21q21), a hybrid intragenic fusion has been reported: HMGIY was fused to the LAMA4 (laminin a4 chain) gene

Abnormal Protein

the HMGIY-LAMA4 resulted from the fusion of the three HMGIY DNA-binding domains with the LAMA4 EGF-like domain

Oncogenesis the exact role of HMGI(Y)-LAMA4 fusion is not established yet Entity Lipomas Disease benign adipocyte tumors Prognosis good Cytogenetics a small subset (5-8%) of ordinary lipomas is characterized by 6p21

rearrangements, the most frequent of which being a reciprocal translocation t(3;6)(q28;p21); in contrast to other benign mesenchymal tumors with 6p21 rearrangement, there is no evidence of HMGIY rearrangements in ordinary lipomas yet; however, to be noticed, the breakpoint on 6p21 was shown to be located whithin a 80 kb region surrounding HMGIY in one lipoma case and HMGIY expression was correlated with 6p rearrangements in two ordinary lipomas and two spindle cell lipomas

Entity Uterine leiomyoma Disease benign mesenchymal tumors Prognosis good Cytogenetics approximately 40% of uterine leiomyomas present structural chromosomal

rearrangements, 5% of which involve 6p abnormalities; they include t(1;6)(q23;p21), t(6;14)(p21;q24) and t(6;10)(p21;q22) as well as inversions and translocations involving other chromosomal partners; the rearrangements are


sometimes complex, only identifiable by FISH analysis Hybrid/Mutated Gene

no hybrid gene has been described yet; as for other mesenchymal tumors, the breakpoint was extragenic, located within a 80 kb region 3' of HMGIY; one case of aberrant transcript with truncation of 1295 bp from the 3' UTR has been described

Abnormal Protein

HMGIY mRNA and protein levels do not always correlate, suggesting that post-transcriptional mechanisms are involved in the regulation of HMGIY

Entity Endometrial polyps Disease uterine benign tumors Prognosis good Cytogenetics several chromosomal abnormalities involving the 6p21.3 region, including

translocations, deletions, inversions have been described; various chromosomal partner regions, such as 14q24, 20q13, 2q35, 10q22, 8q12, 1p32, 7p15, 15q21, have been described to be associated with 6p21.3 in reciprocal translocations.

Hybrid/Mutated Gene

no hybrid gene has been described yet; as for other mesenchymal tumors, the breakpoint is extragenic, located within a 80 kb region 3' of HMGIY

Entity Hamartoma of the breast Disease benign tumor-like nodule of the breast, also called adenolipoma Prognosis good Cytogenetics one case with a t(1 ;6)(p21 ;21), involving the HMGIY gene has been described Entity Microfollicular adenoma of the thyroid Disease epithelial tumors Prognosis favorable Cytogenetics one case with a t(1;6)(p35;21) correlated with an overexpression of HMGIY has

been described


Hugo HMGIY GDB HMGA1 Entrez_Gene HMGA1 3159 high mobility group AT-hook 1

Cards Atlas HMGIYID221 GeneCards HMGA1 Ensembl HMGA1 CancerGene HMGA1 Genatlas HMGA1


GeneLynx HMGA1 eGenome HMGA1 euGene 3159


GoldenPath HMGA1 - 6p21.3 chr6:34312628-34321986 + 6p21.31 (hg17-May_2004)

Ensembl HMGA1 - 6p21.31 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene HMGA1

Gene and transcription Genbank AL354740 [ SRS ] AL354740 [ ENTREZ ] Genbank L17131 [ SRS ] L17131 [ ENTREZ ] Genbank AF176039 [ SRS ] AF176039 [ ENTREZ ] Genbank AK096863 [ SRS ] AK096863 [ ENTREZ ] Genbank AK130027 [ SRS ] AK130027 [ ENTREZ ] RefSeq NM_002131 [ SRS ] NM_002131 [ ENTREZ ] RefSeq NM_145899 [ SRS ] NM_145899 [ ENTREZ ] RefSeq NM_145901 [ SRS ] NM_145901 [ ENTREZ ] RefSeq NM_145902 [ SRS ] NM_145902 [ ENTREZ ] RefSeq NM_145903 [ SRS ] NM_145903 [ ENTREZ ] RefSeq NM_145904 [ SRS ] NM_145904 [ ENTREZ ] RefSeq NM_145905 [ SRS ] NM_145905 [ ENTREZ ] RefSeq NT_086693 [ SRS ] NT_086693 [ ENTREZ ] AceView HMGA1 AceView - NCBI TRASER HMGA1 Traser - Stanford Unigene Hs.518805 [ SRS ] Hs.518805 [ NCBI ] HS518805 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt P17096 [ SRS] P17096 [ EXPASY ] P17096 [ INTERPRO ] Prosite PS00354 HMGI_Y [ SRS ] PS00354 HMGI_Y [ Expasy ] Interpro IPR000637 A+T_hook [ SRS ] IPR000637 A+T_hook [ EBI ] Interpro IPR000116 Highmoblty_IY [ SRS ] IPR000116 Highmoblty_IY [ EBI ] CluSTr P17096

Pfam PF02178 AT_hook [ SRS ] PF02178 AT_hook [ Sanger ] pfam02178 [ NCBI-CDD ]

Prodom PD005593 Highmoblty_IY[INRA-Toulouse]

Prodom P17096 HMGI_HUMAN [ Domain structure ] P17096 HMGI_HUMAN [ sequences sharing at least 1 domain ]

Blocks P17096


PDB 2EZD [ SRS ] 2EZD [ PdbSum ], 2EZD [ IMB ] PDB 2EZE [ SRS ] 2EZE [ PdbSum ], 2EZE [ IMB ] PDB 2EZF [ SRS ] 2EZF [ PdbSum ], 2EZF [ IMB ] PDB 2EZG [ SRS ] 2EZG [ PdbSum ], 2EZG [ IMB ]

Polymorphism : SNP, mutations, diseases OMIM 600701 [ map ] GENECLINICS 600701 SNP HMGA1 [dbSNP-NCBI] SNP NM_002131 [SNP-NCI] SNP NM_145899 [SNP-NCI] SNP NM_145901 [SNP-NCI] SNP NM_145902 [SNP-NCI] SNP NM_145903 [SNP-NCI] SNP NM_145904 [SNP-NCI] SNP NM_145905 [SNP-NCI] SNP HMGA1 [GeneSNPs - Utah] HMGA1 [SNP - CSHL] HMGA1] [HGBASE - SRS]

General knowledge Family Browser HMGA1 [UCSC Family Browser]

SOURCE NM_002131 SOURCE NM_145899 SOURCE NM_145901 SOURCE NM_145902 SOURCE NM_145903 SOURCE NM_145904 SOURCE NM_145905 SMD Hs.518805 SAGE Hs.518805 Amigo function|AT DNA binding Amigo function|DNA binding Amigo process|DNA unwinding Amigo component|chromatin

Amigo process|chromosome organization and biogenesis (sensu Eukaryota)

Amigo component|extracellular region

Amigo function|ligand-dependent nuclear receptor transcription coactivator activity

Amigo function|lipid binding Amigo process|lipid transport


Amigo process|lipoprotein metabolism Amigo process|loss of chromatin silencing Amigo process|nucleosome disassembly Amigo component|nucleus Amigo function|peroxisome proliferator activated receptor binding Amigo process|positive regulation of transcription Amigo process|protein complex assembly Amigo process|regulation of transcription, DNA-dependent Amigo process|regulation of transcription, DNA-dependent Amigo function|retinoid X receptor binding Amigo function|transcription factor activity Amigo component|transcription factor complex PubGene HMGA1

Other databases Probes

Probe Cancer Cytogenetics (Bari) Probe HMGIY Related clones (RZPD - Berlin)

PubMed PubMed 25 Pubmed reference(s) in LocusLink

BibliographyOrganization, inducible-expression and chromosome localization of the human HMG-I(Y) nonhistone protein gene.Friedman M, Holth LT, Zoghbi HY, Reeves R. Nucleic Acids Res 1993; 21: 4259-4267. High level expression of the HMGI(Y) gene during embryonic development.Chiappetta G, Avantaggiato V, Visconti R, Fedele M, Battista S, Trapasso F, Merciai BM, Fidanza V, Giancotti V, Santoro M, Simeone A, Fusco A. Oncogene 1996; 13: 2439-2446. Misexpression of disrupted HMGI architectural factors activates alternative patways of tumorigenesis.Tkachenko A, Ashar HR, Meloni AM, Sandberg AA, Chada KK. Cancer Res 1997; 57: 2276-2280 Hamartoma of the breast with involvement of 6p21 and rearrangement of HMGIY.Dal Cin P, Wanschura S, Christiaens M, Van den Berghe I, Moerman P, Polito P, Kazmierczak B, Bullerdiek J, Van den Berghe H. Genes Chromosomes Cancer 1997; 20: 90-92. HMGI(Y) activation by chromosome 6p21 rearrangements in multilineage


mesenchymal cells from pulmonary hamartomaXiao S, Lux ML, Reeves R, Hudson TJ, Fletcher JA. Am J Pathol 1997; 150: 901-910. Expression of HMGI-C and HMGI(Y) in ordinary lipoma and atypical lipomatous tumors Immunohistochemical reactivity correlates with karyotypic alterations.Tallini G, Dal Cin P, Rhoden KJ, Chiapetta G, Manfioletti G, Giancotti V, Fusco A, Van den Berghe H, Sciot R. Am J Pathol 1997; 151: 37-43. HMGI(Y) expression in human uterine leiomyomata. Involvement of another high-mobility group architectural factor in a benign neoplasm.Williams AJ, Powell WL, Collins T, Morton CC. Am J Pathol 1997; 150: 911-918. Intranuclear distribution of HMGI/Y proteins. An immunocytochemical study.Martelli AM, Riccio M, Bareggi R, Manfioletti G, Tabellini G, Baldini G, Narducci P, Giancotti V. J Histochem Cytochem 1998; 46: 863-864. A role for the architectural transcription factors HMGI(Y) in cytokine gene transcription in T cells.Shannon MF, Himes SR, Attema J. Immunol Cell Biol 1998; 76: 461-466. Expression of HMGI(Y) proteins in squamous intraepithelial and invasive lesions of the uterine cervix.Bandiera A, Bonifacio D, Manfioletti G, Mantovani F, Rustighi A, Zanconati F, Fusco A, Di Bonito L, Giancotti V. Cancer Res 1998; 58: 426-431. Chromosomal translocations in benign tumors : the HMGI proteins.Hess JL. Am J Clin Pathol 1998; 251-261 (Review). HMGIY is the target of 6p21.3 rearrangements in various benign mesenchymal tumors.Kazmierczak B, Dal Cin P, Wanschura S, Borrmann L, Fusco A, Van den Berghe H, Bullerdiek J. Genes Chromosomes Cancer 1998; 23: 279-285. high frequency of tumors with rearrangements of genes of the HMGI(Y) family in a series of 191 pulmonary chondroid hamartomas.Kazmierczak B, Meyer-Bolte K, Tran KH, Wockel W, Breightman I, Rosigkeit J, Bartnitzke S, Bullerdiek J. A. Genes Chromosomes Cancer 1999; 26: 125-133.


Genetics of uterine leiomyomata.Pedeutour F, Ligon AH, Morton CC. Bull Cancer. 1999 86:920-8. Review. Misexpression of wild-type and truncated isoforms of the high-mobility group I proteins HMGI-C and HMGI(Y) in uterine leiomyomas.Klotzbucher M, Wasserfall A, Fuhrmann U. Am J Pathol 1999; 155: 1535-1542. Expression of HMGIY in three uterine leiomyomata with complex rearrangements of chromosome 6.Sornberger KS, Weremowicz S, Williams AJ, Quade BJ, Ligon AH, Pedeutour F, Vanni R, Morton CC. Cancer Genet Cytogenet 1999; 114: 9-16. Involvement of the HMGI(Y) gene in a microfollicular adenoma of the thyroid.Dal Cin P, Fusco A, Belge G, Chiapetta G, Fedele M, Pauwels P, Bullerdiek J, Van den Berghe H. Genes Chromosomes cancer 1999; 24: 286-289. The role of HMGI (Y) in the assembly and function of the IFN-b enhanceosome.Yie J, Merika M, Munshi N, Chen G, Thanos D. EMBO J 1999; 18: 3074-3089. Differential in vivo modifications of the HMGI(Y) nonhistone chromatin proteins modulate nucleosome and DNA interactions.Banks GC, Li Y, Reeves R. Biochemistry 2000; 39: 8333-4836. HMGI-C and HMGI(Y) immunoreactivity correlates with cytogenetic abnormalities in lipomas, pulmonary chondroid hamartomas, endometrial polyps, and uterine leiomyomas and is compatible with rearrangement of the HMGI-C and HMGI(Y) genes.Tallini G, Vanni R, Manfioletti G, Kazmierczak B, Faa G, Pauwels P, Bullerdiek J, Giancotti V, Van Den Berghe H, Dal Cin P. Lab Invest 2000; 80: 359-369. REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST


Contributor(s)Written 11-

2000 Gilka J.F. Gattas, Florence Pedeutour

CitationThis paper should be referenced as such : Gattas GJF, Peudetour F . HMGIY (High mobility group protein (non histone chromosomal) isoform I and Y). Atlas Genet Cytogenet Oncol Haematol. November 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/HMGIYID221.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



PU.1

IdentityOther names SPI-1

Hugo SPI1 Location 11p11-22

DNA/RNA

Description genomic locus around 50kb; 5 exons Transcription 1,4kb. open reading frame (ORF): 991bp

Protein


Description 264 amino acids. DNA binding protein with a ETS consensus motif Expression hematopoietic specific; mainly in B lymphocytes and myeloid lineages;

faintly expressed in erythroid progenitors Localisation nuclear Function transcriptional regulator; specific DNA binding sites with a G/AGAA

minimal element in promoter and enhancers of myeloid and B lymphoid genes; involved both in transcriptional regulation of genes and in splicing regulation of pre-mRNAs

Homology ETS genes family

MutationsGerminal unknown Somatic unknown in human pathologies and cancers; insertional mutagenesis in

murine erythroleukemia

Implicated inEntity Oncogenesis in mouse; mouse gene name: Spi-1 (SFFV Proviral

Integration 1) Disease murine acute erythroleukemia induced by the Friend retrovirus SFFV

(Spleen Focus Forming Virus) Prognosis 100% Hybrid/Mutated Gene no

Abnormal Protein No; overexpression of the normal protein in the proerythroblast


Hugo SPI1 GDB SPI1

Entrez_Gene SPI1 6688 spleen focus forming virus (SFFV) proviral integration oncogene spi1

Cards Atlas SPI1ID269 GeneCards SPI1 Ensembl SPI1 CancerGene SPI1 Genatlas SPI1 GeneLynx SPI1 eGenome SPI1 euGene 6688


Genomic and cartography GoldenPath SPI1 - chr11:47332988-47356674 - 11p11.2 (hg17-May_2004) Ensembl SPI1 - 11p11.2 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene SPI1

Gene and transcription Genbank X52056 [ SRS ] X52056 [ ENTREZ ] RefSeq NM_003120 [ SRS ] NM_003120 [ ENTREZ ] RefSeq NT_086780 [ SRS ] NT_086780 [ ENTREZ ] AceView SPI1 AceView - NCBI TRASER SPI1 Traser - Stanford Unigene Hs.502511 [ SRS ] Hs.502511 [ NCBI ] HS502511 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt P17947 [ SRS] P17947 [ EXPASY ] P17947 [ INTERPRO ] Prosite PS00345 ETS_DOMAIN_1 [ SRS ] PS00345 ETS_DOMAIN_1 [ Expasy ]

Prosite PS00346 ETS_DOMAIN_2 [ SRS ] PS00346 ETS_DOMAIN_2 [ Expasy ]

Prosite PS50061 ETS_DOMAIN_3 [ SRS ] PS50061 ETS_DOMAIN_3 [ Expasy ]

Interpro IPR000418 Ets [ SRS ] IPR000418 Ets [ EBI ] Interpro IPR002341 HSF_ETS [ SRS ] IPR002341 HSF_ETS [ EBI ]

Interpro IPR009058 Wing_hlx_DNA_bnd [ SRS ] IPR009058 Wing_hlx_DNA_bnd [ EBI ]

CluSTr P17947 Pfam PF00178 Ets [ SRS ] PF00178 Ets [ Sanger ] pfam00178 [ NCBI-CDD ] Smart SM00413 ETS [EMBL] Blocks P17947

Polymorphism : SNP, mutations, diseases OMIM 165170 [ map ] GENECLINICS 165170 SNP SPI1 [dbSNP-NCBI] SNP NM_003120 [SNP-NCI] SNP SPI1 [GeneSNPs - Utah] SPI1 [SNP - CSHL] SPI1] [HGBASE - SRS]

General knowledge Family Browser SPI1 [UCSC Family Browser]

SOURCE NM_003120 SMD Hs.502511 SAGE Hs.502511


Amigo process|negative regulation of transcription from Pol II promoter Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo function|transcription factor activity PubGene SPI1


Probe SPI1 Related clones (RZPD - Berlin) PubMed


BibliographySpi-1 is a putative oncogene in virally induced murine erythroleukemia.Moreau-Gachelin, F., Tavitian A, Tambourin P. Nature (London) 1988; 331: 277-280. Medline 88094737 The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene.Klemsz MJ, McKercher SR, Celada A, Van Beveren C, Maki A. Cell 1990; 61: 113-124. Medline 90199884 Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities.McKercher SR, Torbett BE, Anderson KL, Henkel GW, Vestal DJ, Baribault H, Klemz M, Feeney AJ, Wu GE, Paige CJ, Maki RA. EMBO J 1996; 20: 5647-5658. Medline 9705182333 Spi-1/PU.1 transgenic mice develop multistep erythroleukemias.Moreau-Gachelin F, Wendling F, Molina T, Denis N, Titeux M, Grimber G, Briand P, Vainchenker W, Tavitian A. Mol Cell Biol 1996; 16: 2453-2463. Medline 96189128 PU.1 functions in a cell-autonomous manner to control the differentiation of multipotential lymphoid-myeloid progenitors.Scott EW, Fisher RC, Olson MC, Kehrli EW, Simon MC, and Singh H. Immunity 1997; 6: 437-447. Medline 97278846 The transcription factor Spi-1/PU.1 interacts with the potential splicing factor TLS.


Hallier M, Lerga A, Barnache S, Tavitian A, Moreau-Gachelin F. J Biol Chem 1998; 273: 4838-4842. Medline 98148018 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed


2000 Françoise Moreau-Gachelin

CitationThis paper should be referenced as such : Moreau-Gachelin F . PU.1. Atlas Genet Cytogenet Oncol Haematol. November 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/SPI1ID269.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



FGFR1 (Fibroblast Growth Factor Receptor 1) (updated: old version not available)

IdentityOther names BFGFR (basic fibroblast growth factor receptor)

FLT2 (FMS-like tyrosine kinase 2) FLG (FMS-like gene) CEK FGFBR N-SAM Hugo FGFR1 Location 8p12

FGFR1 (8p12) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

Laboratories willing to validate the probes are welcome : contact [email protected]

DNA/RNATranscription 2.7 mRNA

Protein


Protein Diagram Description 822 amino acids; 100-135 kDa glycoprotein from a 90-115 kDa protein

core; tyrosine kinase receptor; contains four major domains: an extracellular domain with 2 or 3 Ig-like loops, a transmembrane domain and an intracellular domain , a juxtamembrane domain, and an intracellular domain composed of the tyrosine kinase domain (two kinase domains interrupted by a short kinase insert), and a C-terminal tail.

Localisation plasma membrane Function FGF receptor with tyrosine kinase activity; binding of ligand (FGF)) in

association with heparan sulfate proteoglycans induces receptor dimerization, autophosphorylation and signal transduction

Homology with other FGFR (FGFR2, FGFR3, and FGFR4)

Implicated inEntity stem-cell myeloproliferative disorder associated with chromosomal

translocations involving 8p12; to date, seven FGFR1 partners have been described (see below)

Disease stem-cell myeloproliferative disorder characterized by T- or B-cell lymphoblastic leukemia/lymphoma, myeloid hyperplasia, and peripheral blood eosinophilia, and it generally progresses to acute myeloid leukemia; specific to the 8p12 chromosomal region

Prognosis very poor (median survival: 12 mths) Cytogenetics the 7 translocations are:

� t(6;8)(q27; p12) involving FOP (FGFR1 Oncogene Partner) � t(8;9)(p12;q33) involving CEP110 (Centrosome protein 110)


� t(8;11)(p12;p15) � t(8;12)(p12;q15) � t(8;13)(p12;q12 ) involving FIM (Fused In Myeloproliferative disorder also called ZNF198 or RAMP) � t(8;17)(p12;q25) � t(8;19)(p12;q13.3) additional anomalies: in the t(8;9)(p12;q33): +der(9), +21; in the t(8;13)(p12;q12): +8, +der(13), +21

Hybrid/Mutated Gene

� 5' FOP - 3' FGFR1 in the t(6;8) � 5'CEP110 - FGFR1 in the t(8;9) � 5' FIM/ZNF198 - 3' FGFR1 in the t(8;13)

Abnormal Protein

three fusion transcripts are identified: FOP-FGFR1, CEP110-FGFR1, and FIM-FGFR1; they encode large proteins containing the N-term of either FOP or CEP110, or FIM, and the catalytic domain of FGFR1 at their C-term: � N-term leucine-rich region from FOP fused to the catalytic domain of FGFR1 � N-term leucine zipper motifs from CEP110 fused to the catalytic domain of FGFR1 � N-term zinc fingers from FIM fused to the Tyrosine kinase domain of FGFR1in C-term

Oncogenesis constitutive activation of FGFR1 Entity Pfeiffer syndrome (inborn disease) Disease one form of Pfeiffer syndrome, an autosomal dominant craniosynostosis

syndrome with broad thumbs and usually no mental deficiency, is due to a mutation in amino acid 252 (Pro252Arg substitution) of FGFR1

Entity Breast cancer Disease gene amplification and overexpression in sporadic breast tumors


Breakpoints


Hugo FGFR1 GDB FGFR1

Entrez_Gene FGFR1 2260 fibroblast growth factor receptor 1 (fms-related tyrosine kinase 2, Pfeiffer syndrome)

Cards Atlas FGFR1113 GeneCards FGFR1 Ensembl FGFR1 CancerGene FGFR1 Genatlas FGFR1 GeneLynx FGFR1 eGenome FGFR1 euGene 2260


GoldenPath FGFR1 - 8p12 chr8:38389449-38445293 - 8p12 (hg17-May_2004)

Ensembl FGFR1 - 8p12 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene FGFR1

Gene and transcription


Genbank A29216 [ SRS ] A29216 [ ENTREZ ] Genbank AY585209 [ SRS ] AY585209 [ ENTREZ ] Genbank AK024388 [ SRS ] AK024388 [ ENTREZ ] Genbank BC015035 [ SRS ] BC015035 [ ENTREZ ] Genbank BC018128 [ SRS ] BC018128 [ ENTREZ ] RefSeq NM_000604 [ SRS ] NM_000604 [ ENTREZ ] RefSeq NM_015850 [ SRS ] NM_015850 [ ENTREZ ] RefSeq NM_023105 [ SRS ] NM_023105 [ ENTREZ ] RefSeq NM_023106 [ SRS ] NM_023106 [ ENTREZ ] RefSeq NM_023107 [ SRS ] NM_023107 [ ENTREZ ] RefSeq NM_023108 [ SRS ] NM_023108 [ ENTREZ ] RefSeq NM_023109 [ SRS ] NM_023109 [ ENTREZ ] RefSeq NM_023110 [ SRS ] NM_023110 [ ENTREZ ] RefSeq NM_023111 [ SRS ] NM_023111 [ ENTREZ ] RefSeq NT_086740 [ SRS ] NT_086740 [ ENTREZ ] AceView FGFR1 AceView - NCBI TRASER FGFR1 Traser - Stanford Unigene Hs.549034 [ SRS ] Hs.549034 [ NCBI ] HS549034 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt P11362 [ SRS] P11362 [ EXPASY ] P11362 [ INTERPRO ] Prosite PS50835 IG_LIKE [ SRS ] PS50835 IG_LIKE [ Expasy ]

Prosite PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 PROTEIN_KINASE_ATP [ Expasy ]

Prosite PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 PROTEIN_KINASE_DOM [ Expasy ]

Prosite PS00109 PROTEIN_KINASE_TYR [ SRS ] PS00109 PROTEIN_KINASE_TYR [ Expasy ]

Interpro IPR007110 Ig-like [ SRS ] IPR007110 Ig-like [ EBI ] Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ] Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ] Interpro IPR001245 Tyr_pkinase [ SRS ] IPR001245 Tyr_pkinase [ EBI ] Interpro IPR008266 Tyr_pkinase_AS [ SRS ] IPR008266 Tyr_pkinase_AS [ EBI ]

CluSTr P11362 Pfam PF00047 ig [ SRS ] PF00047 ig [ Sanger ] pfam00047 [ NCBI-CDD ]

Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI-CDD ]

Prodom PD000001 Prot_kinase[INRA-Toulouse]

Prodom P11362 FGR1_HUMAN [ Domain structure ] P11362 FGR1_HUMAN [ sequences sharing at least 1 domain ]

Blocks P11362


PDB 1AGW [ SRS ] 1AGW [ PdbSum ], 1AGW [ IMB ] PDB 1CVS [ SRS ] 1CVS [ PdbSum ], 1CVS [ IMB ] PDB 1EVT [ SRS ] 1EVT [ PdbSum ], 1EVT [ IMB ] PDB 1FGI [ SRS ] 1FGI [ PdbSum ], 1FGI [ IMB ] PDB 1FGK [ SRS ] 1FGK [ PdbSum ], 1FGK [ IMB ] PDB 1FQ9 [ SRS ] 1FQ9 [ PdbSum ], 1FQ9 [ IMB ] PDB 2FGI [ SRS ] 2FGI [ PdbSum ], 2FGI [ IMB ]

Polymorphism : SNP, mutations, diseases OMIM 136350 [ map ] GENECLINICS 136350 SNP FGFR1 [dbSNP-NCBI] SNP NM_000604 [SNP-NCI] SNP NM_015850 [SNP-NCI] SNP NM_023105 [SNP-NCI] SNP NM_023106 [SNP-NCI] SNP NM_023107 [SNP-NCI] SNP NM_023108 [SNP-NCI] SNP NM_023109 [SNP-NCI] SNP NM_023110 [SNP-NCI] SNP NM_023111 [SNP-NCI] SNP FGFR1 [GeneSNPs - Utah] FGFR1 [SNP - CSHL] FGFR1] [HGBASE - SRS]

General knowledge Family Browser FGFR1 [UCSC Family Browser]

SOURCE NM_000604 SOURCE NM_015850 SOURCE NM_023105 SOURCE NM_023106 SOURCE NM_023107 SOURCE NM_023108 SOURCE NM_023109 SOURCE NM_023110 SOURCE NM_023111 SMD Hs.549034 SAGE Hs.549034

Enzyme 2.7.1.112 [ Enzyme-SRS ] 2.7.1.112 [ Brenda-SRS ] 2.7.1.112 [ KEGG

] 2.7.1.112 [ WIT ] Amigo function|ATP binding


Amigo process|MAPKKK cascade Amigo function|fibroblast growth factor receptor activity Amigo process|fibroblast growth factor receptor signaling pathway Amigo function|heparin binding Amigo component|integral to plasma membrane Amigo process|protein amino acid phosphorylation Amigo process|protein amino acid phosphorylation Amigo function|protein serine/threonine kinase activity Amigo function|protein-tyrosine kinase activity Amigo function|protein-tyrosine kinase activity Amigo function|receptor activity Amigo process|skeletal development Amigo function|transferase activity PubGene FGFR1


Probe Cancer Cytogenetics (Bari) Probe FGFR1 Related clones (RZPD - Berlin)


BibliographyPurification and complementary DNA cloning of a receptor for basic fibroblast growth factor.Lee PL, Johnson DE, Cousens LS, Fried VA, Williams LT. Science 1989; 245: 57-60. Medline 89298406 The complete amino acid sequence of the shorter form of human basic fibroblast growth factor receptor deduced from its cDNA.Itoh N, Terachi T, Ohta M, Seo MK. Biochem Biophys Res Commun 1990;169: 680-685. Medline 90290512 The human fibroblast growth factor receptor genes: a common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain.Johnson DE, Lu J, Chen H, Werner S, Williams LT. Mol Cell Biol 1991; 11: 4627-4634. Medline 91342665 cDNA cloning and expression of a human FGF receptor which binds acidic and


basic FGF.Wennstrom S, Sandstrom C, Claesson-Welsh L. Growth Factors 1991; 4: 197-208. Medline 92118394 Structural and functional diversity in the FGF receptor multigene family.Johnson DE, Williams LT. Adv Cancer Res 1993; 60:1-41. FGFR activation in skeletal disorders: too much of a good thing.Webster MK, Donoghue DJ. Trends Genet 1997; 13: 178-182. Medline 97298558 Differential expression assay of chromosome arm 8p genes identifies Frizzled-related (FRP1/FRZB) and Fibroblast Growth Factor Receptor 1 (FGFR1) as candidate breast cancer genes.Ugolini F, AdŽla•de J, Charafe-Jauffret E, Nguyen C, Jacquemier J, Jordan B, Birnbaum D, PŽbusque MJ. Oncogene 1999; 18: 1903-1910. REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed


1998 Jean-Loup Huret

Updated 12-2000 Marie-Josèphe Pébusque

CitationThis paper should be referenced as such : Huret JL . FGFR1 (Fibroblast Growth Factor Receptor 1). Atlas Genet Cytogenet Oncol Haematol. March 1998 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/FGFR1113.html Pébusque MJ . FGFR1 (Fibroblast Growth Factor Receptor 1). Atlas Genet Cytogenet Oncol Haematol. December 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/FGFR1113.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



MLL (myeloid/lymphoid or mixed lineage leukemia) (updated: old version not available)

IdentityOther names ALL1, HRX, Htrx (human trithorax), TRX1

Hugo MLL Location 11q23 telomeric to PLZF, centromeric from RCK

MLL partner genes - Rolf Marschalek Nov 2002.


DNA/RNA

MLL (11q23) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.


Description 37 exons, spanning over 100 kb Transcription in a centromeric to telomeric direction; 13 and 15 kb; coding sequence:

11.9 kb

Protein

Description 3969 amino acids; 431 KDa; contains from N-term to C-term 3 AT hooks homologous to high mobility group proteins HMGA1 and HMGA2, binding to the minor grove of DNA; 2 speckled nuclear localisation signals; 2 repression domains RD1 and RD2: RD1 or CXXC: cystein


methyl transferase, binds CpG rich DNA, has a transcriptional repression activity; RD2 recruits histone desacetylases HDAC1 and 2; 3 plant homeodomains (cystein rich zinc finger domains, with homodimerization properties), 1 bromodomain (may bind acetylated histones), and 1 plant homeodomain; these domains may be involved in protein-protein interaction; a FYRN and a FRYC domain; a transactivation domain which binds CBP ; may acetylates H3 and H4 in the HOX area; a SET domain: methyltransferase; methyltates H3, including histones in the HOX area for allowing chromatin to be open to transcription. MLL is cleaved by taspase 1 into 2 proteins before entering the nucleus: a p300/320 N-term protein called MLL-N, and a p180 C-term protein, called MLL-C. The FYRN and a FRYC domains of native MLL associate MLL-N and MLL-C in a stable complex; they form a multiprotein complex with transcription factor TFIID.

Expression wide; especially in: brain, kidney, thyroid; expressed in Taned B lymphocytes and myeloid cells

Localisation nuclear, in punctate spots Function transcriptional regulatory factor; MLL may have yin-yang functions

though actions of MLL-N and MLL-C (e.g. desacetylation/acetylation); MLL-N acts as a transcriptional repressor; MLL can be associated with more than 30 proteins, including the core components of the SWI/SNF chromatin remodeling complex and the transcription complex TFIID. MLL binds promotors of HOX genes through acetylation and methylation of histones. MLL is a major regulator of hematopoesis and embryonic development, through regulation of HOX genes expression regulation ( HOXA9 in particular).

Homology trithorax (Drosophila), ALR (human), MLL2 (human)

MutationsNote MLL is implicated in at least 10 % of acute leukaemias (AL) of various

types: acute lymphoblastic leukemias (ALL), acute non lymphocytic leukemias (ANLL), biphenotypic ALs, treatment related leukemias, infant leukemias; the prognosis is poor

Implicated inEntity t(4;11)(q21;q23)/acute leukaemias --> MLL-AFF1 (AF4) Disease typically CD19+ CD10-precursor B-ALL, biphenotypic AL, at times

ANLL (M4/M5); common in infants may be congenital; treatment related leukaemia (secondary to epipodophyllotoxins)

Prognosis median survival < 1yr Cytogenetics additional chromosome anomalies are found in 1/4 of cases, one of

which is the i(7q) Hybrid/Mutated Gene 5' MLL-3' AF4; 12kb

Abnormal Protein

240 kDa protein with about 1400 aminoacids from NH2 MLL and 850 from COOH AF4 (variable breakpoints); the reciprocal may or may not be expressed


Entity t(6;11)(q27;q23) /ANLL -->MLL- MLLT4 (AF6) Disease M5/M4 de novo and therapy related ANLL, T-cell ALL Prognosis poor Entity t(9;11) (p22;q23)/ANLL -->MLL-MLLT3 (AF9) Disease M5/M4 de novo and therapy related ANLL Prognosis the prognosis may not be as poor as in other 11q23 leukaemias in de

novo cases; very poor prognosis in secondary ANLL cases Cytogenetics may be overlooked; often as a sole anomaly Hybrid/Mutated Gene variable breakpoints on both genes

Abnormal Protein

N-term -- AT hook and DNA methyltransferase from MLL fused to the 192 C-term amino acids from AF9 (as breakpoints are variable, this is only an example)

Entity t(10;11)(p12;q23) /ANLL --> MLL- MLLT10 (AF10) Disease M4 or M5 ANLL; ALL at times; therapy related ANLL Prognosis poor Entity t(11;19)(q23;p13.1) /ANLL --> MLL-ELL Disease mainly M4/M5; treatment related leukemia; all ages Prognosis very poor Cytogenetics detected with R banding Hybrid/Mutated Gene 5' MLL - 3' ELL

Abnormal Protein AT hook and DNA methyltransferase from MLL fused to most of ELL

Oncogenesis potential transcription factor Entity t(11;19)(q23;p13.3) /acute leukaemias --> MLL-MLLT1 (ENL) Disease ALL (CD19+), biphenotypic AL, ANLL (M4/M5); mainly congenital;

treatment-related leukaemia Prognosis very poor, except in rare T-cell cases Cytogenetics detected with G banding Hybrid/Mutated Gene 5' MLL - 3' ENL

Abnormal Protein

AT hook and DNA methyltransferase from MLL fused to, most often, the nearly entire ENL


Entity Other entities: � t(X;11)(q13;q23)/ANLL, T-ALL --> MLL - AFX1 � t(X;11)(q22;q23)/ANLL --> MLL- Septin2 � t(1;11)(p32;q23)/ALL --> MLL- EB15 (AF1p) � t(1;11)(q21;q23)/ANLL --> MLL- MLLT11 (AF1q) � t(2;11)(q11;q23)/ALL --> MLL- AFF3 (LAF4) � t(3;11)(p21;q23)/t-ANLL, ALL--> MLL- NCKIPSD (AF3p21) � t(3;11)(q21;q23)/ALL --> MLL- EEFSEC (SELB) � t(3;11)(q25;q23)/t-ANLL --> MLL - GMPS � t(3;11)(q28;q23)/ANLL --> MLL - LPP � t(4;11)(p12;q23) --> MLL - AF4p12 � t(4;11)(q12;q23) --> MLL - MIFL � t(4;11)(q21;q23)/atypical CML --> MLL - SEPT11 � t(4;11)(q35;q23)--> MLL - ArgBP2 � t(5;11)(q31;q23)/ANLL, ALL --> MLL - ARHGAP26 (GRAF) � ins(5;11)(q31;q13q23)/ALL --> MLL - AFF4 (AF5q31) � t(6;11)(q12;q23)/ANLL --> MLL - SMAP1 � t(6;11)(q21;q23)/ANLL --> MLL - FOXO3A (AF6q21) � t(9;11)(q34;q23)/ANLL --> MLL - DAB2IP (AF9q34) � t(10;11)(p11;q23)/ANLL --> MLL - ABI1 � t(10;11)(q21;q23)/ANLL --> MLL - CXXC6 (TET1) � t(11;11)(q21;q23)/ANLL --> MLL - PICALM � trisomy 11/ANLL --> MLL tandem duplication � t(11;11)(q23;q23)/ANLL --> MLL - CBL � t(11;11)(q23;q23)/ANLL --> MLL - ARHGEF12 (LARG) � t(11;11)(q23;q24)/ANLL --> MLL - TIRAP � t(11;12)(q23;q13)/ANLL --> MLL - CIP29 � t(11;14)(q23;q24)/ANLL, AUL --> MLL - GPHN � t(11;15)(q23;q14)/ANLL, ALL --> MLL - CASC5 (AF15q14) � t(11;15)(q23;q14) --> MLL - MPFYVE � t(11;15)(q23;q15) --> MLL - AF15 � t(11;16)(q23;p13)/MDS, ANLL, t-ANLL, ALL --> MLL - CREBBP (CBP) � t(11;17)(q23;p13)/t-ANLL --> MLL - GAS7 � t(11;17)(q23;q21)/ANLL --> MLL - ACACA � t(11;17)(q23;q21)/ANLL --> MLL - LASP1 � t(11;17)(q23;q21)/ ANLL --> MLL - MLLT6 (AF17) � t(11;17)(q23;q21)/ANLL --> MLL - RARa � t(11;17)(q23;q25)/ MDS, ANLL --> MLL - SEPT9 (MSF1, AF17q25) � t(11;19)(q23;p13)/ANLL --> MLL - SH3GLI1 (EEN) � t(11;19)(q23;p13)/ANLL --> MLL - MYO1F � t(11;20)(q23;q11)/ALL --> MLL - MAPRE1 (EB1) � t(11;22)(q23;q11.2)/ANLL --> MLL - SEPT5 (hCDCRel) � t(11;22)(q23;q13) /ANLL --> MLL - EP300 (P300)

Breakpoints


Note spanning a 8 kb genomic region; between exons 5 to 11; highly variable on the partner,

ranging from close to the NH2-term in MLLT1 (ENL), to near the COOH-term in MLLT3 (AF9)

To be noted the card on 11q23 rearrangements, gives an overview on diseases

implicating MLL, as welle as 11q23 rearrangements in therapy related leukaemias See also 11q23 rearrangements in childhood acute lymphoblastic leukemia: Clinical aspects and congenital leukemias


Hugo MLL GDB MLL

Entrez_Gene MLL 4297 myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila)

Cards


Atlas MLL GeneCards MLL Ensembl MLL CancerGene MLL Genatlas MLL GeneLynx MLL eGenome MLL euGene 4297


GoldenPath MLL - 11q23 chr11:117812415-117901146 + 11q23.3 (hg17-May_2004)

Ensembl MLL - 11q23.3 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MLL

Gene and transcription Genbank AF036405 [ SRS ] AF036405 [ ENTREZ ] Genbank AY373585 [ SRS ] AY373585 [ ENTREZ ] Genbank U04737 [ SRS ] U04737 [ ENTREZ ] Genbank X83604 [ SRS ] X83604 [ ENTREZ ] Genbank Z69744 [ SRS ] Z69744 [ ENTREZ ] RefSeq NM_005933 [ SRS ] NM_005933 [ ENTREZ ] RefSeq NT_086787 [ SRS ] NT_086787 [ ENTREZ ] AceView MLL AceView - NCBI TRASER MLL Traser - Stanford Unigene Hs.258855 [ SRS ] Hs.258855 [ NCBI ] HS258855 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt Q03164 [ SRS] Q03164 [ EXPASY ] Q03164 [ INTERPRO ]

Prosite PS50014 BROMODOMAIN_2 [ SRS ] PS50014 BROMODOMAIN_2 [ Expasy ]

Prosite PS50868 POST_SET [ SRS ] PS50868 POST_SET [ Expasy ] Prosite PS50280 SET [ SRS ] PS50280 SET [ Expasy ] Prosite PS01359 ZF_PHD_1 [ SRS ] PS01359 ZF_PHD_1 [ Expasy ] Prosite PS50016 ZF_PHD_2 [ SRS ] PS50016 ZF_PHD_2 [ Expasy ] Interpro IPR001487 Bromodomain [ SRS ] IPR001487 Bromodomain [ EBI ] Interpro IPR003889 FYrich_C [ SRS ] IPR003889 FYrich_C [ EBI ] Interpro IPR003888 FYrich_N [ SRS ] IPR003888 FYrich_N [ EBI ] Interpro IPR003616 PostSET [ SRS ] IPR003616 PostSET [ EBI ] Interpro IPR001214 SET [ SRS ] IPR001214 SET [ EBI ]


Interpro IPR002857 Znf_CXXC [ SRS ] IPR002857 Znf_CXXC [ EBI ] Interpro IPR001965 Znf_PHD [ SRS ] IPR001965 Znf_PHD [ EBI ] CluSTr Q03164

Pfam PF02178 AT_hook [ SRS ] PF02178 AT_hook [ Sanger ] pfam02178 [ NCBI-CDD ]

Pfam PF05965 FYRC [ SRS ] PF05965 FYRC [ Sanger ] pfam05965 [ NCBI-CDD ]

Pfam PF05964 FYRN [ SRS ] PF05964 FYRN [ Sanger ] pfam05964 [ NCBI-CDD ]

Pfam PF00628 PHD [ SRS ] PF00628 PHD [ Sanger ] pfam00628 [ NCBI-CDD ] Pfam PF00856 SET [ SRS ] PF00856 SET [ Sanger ] pfam00856 [ NCBI-CDD ]

Pfam PF02008 zf-CXXC [ SRS ] PF02008 zf-CXXC [ Sanger ] pfam02008 [ NCBI-CDD ]

Smart SM00384 AT_hook [EMBL] Smart SM00297 BROMO [EMBL] Smart SM00542 FYRC [EMBL] Smart SM00541 FYRN [EMBL] Smart SM00249 PHD [EMBL] Smart SM00508 PostSET [EMBL] Smart SM00317 SET [EMBL] Blocks Q03164

Polymorphism : SNP, mutations, diseases OMIM 159555 [ map ] GENECLINICS 159555 SNP MLL [dbSNP-NCBI] SNP NM_005933 [SNP-NCI] SNP MLL [GeneSNPs - Utah] MLL [SNP - CSHL] MLL] [HGBASE - SRS]

General knowledge Family Browser MLL [UCSC Family Browser]

SOURCE NM_005933 SMD Hs.258855 SAGE Hs.258855 Amigo function|DNA binding Amigo function|RNA polymerase II transcription factor activity Amigo component|nucleus Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo function|transcription factor activity Amigo process|transcription from Pol II promoter Amigo function|zinc ion binding


PubGene MLL Other databases Probes

Probe MLL1 (11q23) in normal cells (Bari) Probe MLL Related clones (RZPD - Berlin)


BibliographySelf-fusion of the ALL1 gene. A new genetic mechanism for acute leukemia.Schichman SA, Canaani E, Croce CM. JAMA 1995; 273: 571-576. Medline 95139200 Molecular basis of 11q23 rearrangements in hematopoietic malignant proliferations.Bernard OA, Berger R. Genes Chromosom Cancer 1995; 13: 75-85. Medline 7542910 Complete exon structure of the ALL1 gene.Rasio D, Schichman SA, Negrini M, Canaani E, Croce CM. Cancer Res 1996; 56: 1766-1769. Medline 8620491 Exon/intron structure of the human ALL-1 (MLL) gene involved in translocations to chromosomal region 11q23 and acute leukaemias.Nilson I, Lochner K, Siegler G, Greil J, Beck JD, Fey GH, Marschalek R. Brit J Haematol 1996; 93: 966-972. Medline 8703835 Chromosome abnormalities in leukaemia: the 11q23 paradigm.Young BD, Saha V. Cancer Surv 1996; 28: 225-245. Medline 97131386 11q23 rearrangements in acute leukemiaRubnitz JE, et al Leukemia 1996; 10: 74-82. Review Medline 96145214 Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax.Prasad R, et al. Oncogene 1997; 15: 549-560.


Medline 97388474 Disruption of a Homolog of Trithorax by 11q23 translocations: leukemogenic and transctiptional implications.Waring PM, Cleary ML. Current Topics Microbiol Immunol 1997; 220: 1-23. Medline 97256982 MLL rearrangements in hematological malignancies: lessons from clinical and biological studies.DiMartino JF, Cleary ML. Br J Haemotol 1999; 106: 614-626. Medline 99398075 MLL2, the second homolog of the Drosophila trithorax gene, maps to 19q13.1 and is amplified in solid tumor lines.Huntsman DG, et al. Oncogene 1999; 18: 7975-7984. Medline 20105772 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed



Updated 12-2000 Jay L Hess, Jean-Loup Huret

Updated 11-2002 Rolf Marschalek

Updated 10-2005 Jean-Loup Huret

CitationThis paper should be referenced as such : Huret JL . MLL (myeloid/lymphoid or mixed lineage leukemia). Atlas Genet Cytogenet Oncol Haematol. December 1997 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MLL.html


Hess JL and Huret JL . MLL (myeloid/lymphoid or mixed lineage leukemia). Atlas Genet Cytogenet Oncol Haematol. December 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MLL.html Marschalek R . MLL (myeloid/lymphoid or mixed lineage leukemia). Atlas Genet Cytogenet Oncol Haematol. November 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MLL.html Huret JL . MLL (myeloid/lymphoid or mixed lineage leukemia). Atlas Genet Cytogenet Oncol Haematol. October 2005 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/MLL.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



PRDX1 (peroxiredoxin 1) (updated: old version not available)

IdentityNote PAGA/NKEFA/PRDX1/peroxiredoxin 1, located in 1p34, is often

confused in databases and elsewhere with PAGB/TDPX2, a pseudogene located in 9p22; PAGB is not either NKEFB/PRDX2/peroxiredoxin 2, located in 13q12; the other peroxiredoxins, PRDX3 and PRDX5, are located in 10q25-26 and in 11q13 respectively

Other names PAGA (Proliferation Associated Gene A)

PAG PRX1 Hs.1163 NKEFA (natural killer-enhancing factor A) Prx-1 (peroxiredoxin 1) HBP23 (Heme-binding protein 23 kDa) MSP23 (macrophage 23-kD stress protein) Hugo PRDX1 Location 1p34.1

DNA/RNADescription 6 exons, 13 kb Transcription 937 bp mRNA; 599 bp coding sequence Pseudogene pseudogene in 9p22

Protein Description 199 amino acids; 22 kDa; form dimers through a disulfide bridge Expression widely expressed, in particular in the various cell types of the central

nervous system and in red blood cells; overexpressed following induction of proliferation and oxidative stress

Localisation cytosolic Function antioxidant, against oxidative stress; Abl SH3-binding protein; inhibitor

of c-Abl tyrosine kinase activity; also binds to heme Homology thioperoxiredoxines

Implicated in


Disease Correlations between the expression level and the stage of tumor progrssion in squamous cell carcinoma of the oral cavity; high expression in follicular thyroid tumors, but not in papillary carcinoma of the thyroid


Hugo PRDX1 GDB PRDX1 Entrez_Gene PRDX1 5052 peroxiredoxin 1

Cards Atlas PAGID266 GeneCards PRDX1 Ensembl PRDX1 CancerGene PAGA Genatlas PRDX1 GeneLynx PRDX1 eGenome PRDX1 euGene 5052


GoldenPath PRDX1 - 1p34.1 chr1:45645801-45656702 - 1p34.1 (hg17-May_2004)

Ensembl PRDX1 - 1p34.1 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene PRDX1

Gene and transcription Genbank AL451136 [ SRS ] AL451136 [ ENTREZ ] Genbank X72296 [ SRS ] X72296 [ ENTREZ ] Genbank AI912389 [ SRS ] AI912389 [ ENTREZ ] Genbank AK131049 [ SRS ] AK131049 [ ENTREZ ] Genbank AV691526 [ SRS ] AV691526 [ ENTREZ ] RefSeq NM_002574 [ SRS ] NM_002574 [ ENTREZ ] RefSeq NM_181696 [ SRS ] NM_181696 [ ENTREZ ] RefSeq NM_181697 [ SRS ] NM_181697 [ ENTREZ ] RefSeq NT_086582 [ SRS ] NT_086582 [ ENTREZ ] AceView PRDX1 AceView - NCBI TRASER PRDX1 Traser - Stanford


Unigene Hs.180909 [ SRS ] Hs.180909 [ NCBI ] HS180909 [ spliceNest ] Protein : pattern, domain, 3D structure

SwissProt Q06830 [ SRS] Q06830 [ EXPASY ] Q06830 [ INTERPRO ] Interpro IPR000866 AhpC-TSA [ SRS ] IPR000866 AhpC-TSA [ EBI ] CluSTr Q06830

Pfam PF00578 AhpC-TSA [ SRS ] PF00578 AhpC-TSA [ Sanger

] pfam00578 [ NCBI-CDD ] Blocks Q06830

Polymorphism : SNP, mutations, diseases OMIM 176763 [ map ] GENECLINICS 176763 SNP PRDX1 [dbSNP-NCBI] SNP NM_002574 [SNP-NCI] SNP NM_181696 [SNP-NCI] SNP NM_181697 [SNP-NCI] SNP PRDX1 [GeneSNPs - Utah] PRDX1 [SNP - CSHL] PRDX1] [HGBASE - SRS]

General knowledge Family Browser PRDX1 [UCSC Family Browser]

SOURCE NM_002574 SOURCE NM_181696 SOURCE NM_181697 SMD Hs.180909 SAGE Hs.180909 Enzyme 1.11.1.- [ Enzyme-SRS ] 1.11.1.- [ Brenda-SRS ] 1.11.1.- [ KEGG ] 1.11.1.- [ WIT ] Amigo process|cell proliferation Amigo function|oxidoreductase activity Amigo function|peroxidase activity Amigo process|skeletal development PubGene PRDX1


Probe PRDX1 Related clones (RZPD - Berlin) PubMed


BibliographyA human cDNA corresponding to a gene overexpressed during cell proliferation encodes a product sharing homology with amoebic and bacterial proteins.


Prosperi MT, Ferbus D, Karczinski I, Goubin G. J Biol Chem 1993; 268: 11050-11056. Medline 93266552 Organization and chromosomal assignment of two human pag gene loci: pagA encoding a functional gene and pagB a processed pseudogene.Prosperi MT, Apiou F, Dutrillaux B, Goubin G. Genomics 1994; 19: 236-241. Cloning and sequence analysis of candidate human natural killer-enhancing factor genes.Shau H, Butterfield LH, Chiu R, Kim A. Immunogenetics 1994; 40: 129-134. Medline 94299283 Identification of natural killer enhancing factor as a major antioxidant in human red blood cells.Shau H, Kim A. Biochem Biophys Res Commun 1994; 199: 83-88. Medline 94168617 Antioxidant function of recombinant human natural killer enhancing factor.Sauri H, Butterfield L, Kim A, Shau H . Biochem Biophys Res Commun 1995; 208: 964-969 . Medline 95217213 Recombinant natural killer enhancing factor augments natural killer cytotoxicity.Sauri H, Ashjian PH, Kim AT, Shau H. J Leukoc Biol 1996; 59: 925-931. Medline 96272232 The PAG gene product, a stress-induced protein with antioxidant properties, is an Abl SH3-binding protein and a physiological inhibitor of c-Abl tyrosine kinase activity.Wen ST, Van Etten RA . Genes Dev 1997; 11: 2456-2467.E Medline 97475823 Characterization of a mammalian peroxiredoxin that contains one conserved cysteine.Kang SW, Baines IC, Rhee SG. J Biol Chem 1998; 273: 6303-6311. Medline 98165813 The pag gene product, a physiological inhibitor of c-abl tyrosine kinase, is


overexpressed in cells entering S phase and by contact with agents inducing oxidative stress.Prosperi MT, Ferbus D, Rouillard D, Goubin G. FEBS Lett 1998; 423: 39-44. Medline 98165683 Expression of the antioxidant gene NKEF in the central nervous system.Sarafian TA, Huang C, Kim A, de Vellis J, Shau H. Mol Chem Neuropathol 1998; 34: 39-51. Medline 98451667 Crystal structure of a multifunctional 2-Cys peroxiredoxin heme-binding protein 23 kDa/proliferation-associated gene product.Hirotsu S, Abe Y, Okada K, Nagahara N, Hori H, Nishino T, Hakoshima T. Proc Natl Acad Sci U S A 1999; 96: 12333-12338. Medline 20006234 Differential expression of peroxiredoxin subtypes in human brain cell types.Sarafian TA, Verity MA, Vinters HV, Shih CC, Shi L, Ji XD, Dong L, Shau H. J Neurosci Res 1999; 56: 206-212. Medline 99425342 Yanagawa T, Ishikawa T, Ishii T, Tabuchi K, Iwasa S, Bannai S, Omura K, Suzuki H, Yoshida H.Peroxiredoxin I expression in human thyroid tumors. Cancer Lett 1999; 145: 127-132. Medline 99458363 Peroxiredoxin I (macrophage 23 kDa stress protein) is highly and widely expressed in the rat nervous system.Mizusawa H, Ishii T, Bannai S. Neurosci Lett 2000; 283: 57-60. Medline 20195765 Peroxiredoxin I expression in oral cancer: a potential new tumor marker.Yanagawa T, Iwasa S, Ishii T, Tabuchi K, Yusa H, Onizawa K, Omura K, Harada H, Suzuki H, Yoshida H. Cancer Lett 2000; 156: 27-35. Medline 20300655 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Contributor(s)


Written 10-2000 Maité P Prosperi, Didier Ferbus, Gérard.Goubin


CitationThis paper should be referenced as such : Prosperi MP, Ferbus D, Goubin G . PRDX1 (peroxiredoxin 1). Atlas Genet Cytogenet Oncol Haematol. October 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PAGID266.html Huret JL . PRDX1 (peroxiredoxin 1). Atlas Genet Cytogenet Oncol Haematol. December 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PAGID266.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



PTCH1 (updated: old version not available)

IdentityOther names PTC, but this term was confusing with PTC/PKA

PTCH patched Hugo PTCH Location 9q22.3

(between FACC and XPAC PTCH1 is flanked by the microsatellite markers D9S196 and D9S287; a microsatellite marker, 1AJL, is located inside the gene

DNA/RNADescription 24 exons, exon 24 is non-coding; 34 kb Transcription alternate splicing: 3 different 5' termini; 6.5 kb mRNA; coding

sequence: CDS 1 ... 4344

Protein Description glycoprotein; 12 transmembrane domains, 2 extra cellular loops,

intracellular N-term and C-term and sterol-sensing domain (SSD) Expression widely expressed at low levels; increased levels in cells receiving a

hedgehog signal Localisation transmembrane protein, cellular membrane, intracellular vesicles Function part of a signalling pathway; opposed by the gene products of hedgehog

genes; transmembrane protein; is thought to have a repressive activity on cell proliferation; the recent demonstration of NBCCS syndrome (see below) as a chromosome instability syndrome suggests that this protein has a role in DNA maintenance, repair and/or replication

Homology patched (drosophila segment polarity gene), PTCH2 (human gene with unknown function)


MutationsGerminal germ-line mutations lead to protein truncation in naevoid basal cell

carcinoma syndrome (NBCCS) patients (see below); mutations types are variable : nucleotide substitutions (missense/nonsense), small deletions, or small insertions mainly, leading to protein truncation; these mutations have been observed in most exons; there is, so far, no hot-spot.

Somatic mutation and allele loss events in basal cell carcinoma, in NBCCS and in sporadic basal cell carcinoma are, so far, in accordance with the two-hit model for neoplasia, as is found in retinoblastoma; mutation and allele loss have also been found in sporadic primitive neuroectodermal tumours (PNETs), sporadic medulloblastomas and in a few cases of esophageal squamous cell carcinoma and invasive transitional cell carcinoma of the bladder; mutations have also been reported in a low frequency of sporadic trichoepitheliomas and in sporadic odontogenic keratocysts

Implicated inEntity naevoid basal cell carcinoma syndrome (NBCCS) or Gorlin syndrome Disease autosomal dominant condition; cancer prone disease (multiple basal

cell carcinomas, medulloblastomas); malformations; it is also a chromosome instability syndrome

Cytogenetics spontaneous and induced chromosome instability Entity skin cancers Disease � sporadic basal cell carcinoma, but also in the benign

trichoepithelioma, a tumor often associated with basal cell carcinomas � sporadic basal cell carcinoma from xeroderma pigmentosum patients have a high frequency of typical UV-induced mutations in PTCH1

Entity brain diseases Disease � in a subset of sporadic primitive neuroectodermal tumours

(PNETs)of the central nervous system (cerebral PNETs, medulloblastomas, and desmoplastic medulloblastomas); note: NBCCS patients have a predisposition for the development of PNETs, while, herein mentioned are sporadic PNETs � PTCH1 have also been found mutated in both familiar and sporadic cases of Holoprosencephaly (HPE)

Entity various cancers and benign tumors Disease � invasive transitional cell carcinoma of the bladder: PTCH1 has been

found mutated in rare cases � sporadic esophageal squamous cell carcinoma � jaws: in sporadic odontogenic keratocysts and in odontogenic


keratocysts from NBCCS patients


Hugo PTCH GDB PTCH Entrez_Gene PTCH 5727 patched homolog (Drosophila)

Cards Atlas PTCH100 GeneCards PTCH Ensembl PTCH CancerGene PTCH Genatlas PTCH GeneLynx PTCH eGenome PTCH euGene 5727


GoldenPath PTCH - 9q22.3 chr9:95285955-95350386 - 9q22.32 (hg17-May_2004)

Ensembl PTCH - 9q22.32 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene PTCH

Gene and transcription Genbank AY395758 [ SRS ] AY395758 [ ENTREZ ] Genbank AY395768 [ SRS ] AY395768 [ ENTREZ ] Genbank AY395772 [ SRS ] AY395772 [ ENTREZ ] Genbank AB189436 [ SRS ] AB189436 [ ENTREZ ] Genbank AB189437 [ SRS ] AB189437 [ ENTREZ ] RefSeq NM_000264 [ SRS ] NM_000264 [ ENTREZ ] RefSeq NT_086752 [ SRS ] NT_086752 [ ENTREZ ] AceView PTCH AceView - NCBI TRASER PTCH Traser - Stanford Unigene Hs.494538 [ SRS ] Hs.494538 [ NCBI ] HS494538 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt Q13635 [ SRS] Q13635 [ EXPASY ] Q13635 [ INTERPRO ] Prosite PS50156 SSD [ SRS ] PS50156 SSD [ Expasy ] Interpro IPR003392 Patched [ SRS ] IPR003392 Patched [ EBI ]


Interpro IPR004766 Patchedtm_recept [ SRS ] IPR004766 Patchedtm_recept [ EBI ]

Interpro IPR000731 SSD_5TM [ SRS ] IPR000731 SSD_5TM [ EBI ] CluSTr Q13635

Pfam PF02460 Patched [ SRS ] PF02460 Patched [ Sanger ] pfam02460 [ NCBI-CDD ]

Blocks Q13635 Polymorphism : SNP, mutations, diseases

OMIM 601309 [ map ] GENECLINICS 601309 SNP PTCH [dbSNP-NCBI] SNP NM_000264 [SNP-NCI] SNP PTCH [GeneSNPs - Utah] PTCH [SNP - CSHL] PTCH] [HGBASE - SRS]

General knowledge Family Browser PTCH [UCSC Family Browser]

SOURCE NM_000264 SMD Hs.494538 SAGE Hs.494538 Amigo process|cell proliferation Amigo function|hedgehog receptor activity Amigo component|integral to plasma membrane Amigo process|morphogenesis Amigo process|negative regulation of cell cycle Amigo function|receptor activity Amigo process|signal transduction BIOCARTA Sonic Hedgehog (SHH) Receptor Ptc1 Regulates cell cycle BIOCARTA Sonic Hedgehog (Shh) Pathway PubGene PTCH

Other databases Other database Locus specific database; PTCH Mutation Database

Probes Probe PTCH Related clones (RZPD - Berlin)


BibliographyThe Drosophila hedgehog gene is expressed specifically in posterior compartment cells and is a target of engrailed regulation.Tabata T, Eaton S, Kornberg TB


Genes Dev 1992 Dec;6(12B):2635-45 Medline 94040725 Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein.Basler K, Struhl G Nature 1994 Mar 17;368(6468):208-14 Medline 94195387 The Drosophila segment polarity gene patched interacts with decapentaplegic in wing development.Capdevila J, Estrada MP, Sanchez-Herrero E, Guerrero I EMBO J 1994 Jan 1;13(1):71-82 Medline 94139676 The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas.Gailani MR, Stahle-Backdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Unden AB, Dean M, Brash DE, Bale AE, Toftgard R Nat Genet 1996 Sep;14(1):78-81 Medline 96376974 A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities.Hahn H, Christiansen J, Wicking C, Zaphiropoulos PG, Chidambaram A, Gerrard B, Vorechovsky I, Bale AE, Toftgard R, Dean M, Wainwright B J Biol Chem 1996 May 24;271(21):12125-8 Medline 96218118 Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ, Gerrard B, Goldstein AM, Dean M, Toftgard R, Chenevix-Trench G, Wainwright B, Bale AE Cell 1996 Jun 14;85(6):841-51 Medline 96279829 Human homolog of patched, a candidate gene for the basal cell nevus syndrome.Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH Jr, Scott MP Science 1996 Jun 14;272(5268):1668-71 Medline 96247324 Characterisation of human patched germ line mutations in naevoid basal cell carcinoma syndrome.


Lench NJ. Telford EA. High AS. Markham AF. Wicking C. Wainwright BJ. Hum Genet. 1997 Oct;100(5-6):497-502. Medline 98001068 Sporadic medulloblastomas contain PTCH mutations.Raffel C, Jenkins RB, Frederick L, Hebrink D, Alderete B, Fults DW, James CD Cancer Res 1997 Mar 1;57(5):842-5 Medline 97193598 Trichoepitheliomas contain somatic mutations in the overexpressed PTCH gene: support for a gatekeeper mechanism in skin tumorigenesis.Vorechovsky I, Unden AB, Sandstedt B, Toftgard R, Stahle-Backdahl M Cancer Res 1997 Nov 1;57(21):4677-81 Medline 98014543 Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident.Wicking C, Shanley S, Smyth I, Gillies S, Negus K, Graham S, Suthers G, Haites N, Edwards M, Wainwright B, Chenevix-Trench G Am J Hum Genet 1997 Jan;60(1):21-6 Medline 97136566 Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system.Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G Cancer Res 1997 Jul 1;57(13):2581-5 Medline 97349054 Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors.Xie J. Johnson RL. Zhang X. Bare JW. Waldman FM. Cogen PH. Menon AG. Warren RS. Chen LC. Scott MP. Epstein EH Jr. Cancer Res 1997 Jun 15; 57(12):2369-72 Medline 97336016 Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome.Aszterbaum M, Rothman A, Johnson RL, Fisher M, Xie J, Bonifas JM, Zhang X, Scott MP, Epstein EH Jr J Invest Dermatol 1998 Jun;110(6):885-8 Medline 98281604 Patching together the genetics of Gorlin syndromeBale SJ, Falk RT, Rogers GR


J Cutan Med Surg 1998 Jul;3(1):31-4 Medline 99088403 Dinucleotide repeat polymorphism within the tumor suppressor gene PTCH at 9q22.Louhelainen J. Lindstrom E. Hemminki K. Toftgard R. Clin Genet 1998 Sep; 54(3):239-41 Medline 99002778 Mutations in the human homologue of the Drosophila patched gene in esophageal squamous cell carcinoma.Maesawa C. Tamura G. Iwaya T. Ogasawara S. Ishida K. Sato N. Nishizuka S. Suzuki Y. Ikeda K. Aoki K. Saito K. Satodate R. Genes Chromosom Cancer 1998; Mar;21(3):276-9 PTCH gene mutations in invasive transitional cell carcinoma of the bladder.McGarvey TW, Maruta Y, Tomaszewski JE, Linnenbach AJ, Malkowicz SB Oncogene 1998 Sep 3;17(9):1167-72 Medline 98435856 Mutations of PATCHED in holoprosencephaly.Ming JE, Kaupas ME, Roessler E, Brunner HG, Nance WE, Stratton RF, Sujansky E, Bale Sj, Muenke M Am J Hum Genet 1998; 63 Suppl 140 The naevoid basal-cell carcinoma syndrome (Gorlin syndrome) is a chromosomal instability syndrome.Shafei-Benaissa E, Savage JR, Babin P, Larregue M, Papworth D, Tanzer J, Bonnetblanc JM, Huret JL Mutat Res 1998 Feb 2;397(2):287-92 Medline 98202735 High levels of patched gene mutations in basal-cell carcinomas from patients with xeroderma pigmentosum.Bodak N. Queille S. Avril MF. Bouadjar B. Drougard C. Sarasin A. Daya-Grosjean L. Proc Natl Acad Sci USA 1999 Apr 27; 96(9):5117-22. Medline 99238492 The hedgehog signalling pathway and its role in basal cell carcinoma. [Review]Booth DR. Cancer & Metastasis Reviews 1999;18(2):261-84 Medline 20191332 PTCH gene mutations in odontogenic keratocysts.Barreto DC. Gomez RS. Bale AE. Boson WL. De Marco L. J Dent Res 2000 Jun; 79(6):1418-22


Medline 20346776 UV-specific mutations of the human patched gene in basal cell carcinomas from normal individuals and xeroderma pigmentosum patients. [Review]Daya-Grosjean L. Sarasin A Mut Res 2000 May 30;450(1-2):193-9 Medline 20299177 UV mutation signature in tumor suppressor genes involved in skin carcinogenesis in xeroderma pigmentosum patients.D'Errico M. Calcagnile A. Canzona F. Didona B. Posteraro P. Cavalieri R. Corona R. Vorechovsky I. Nardo T. Stefanini M. Dogliotti E. Oncogene 2000 Jan 20;19(3):463-7 Medline 20120488 Identification of PATCHED mutations in medulloblastomas by direct sequencing.Dong J. Gailani MR. Pomeroy SL. Reardon D. Bale AE. Hum Mut 2000 Jul;16(1):89-90 Medline 20334946 The spectrum of patched mutations in a collection of Australian basal cell carcinomas.Evans T. Boonchai W. Shanley S. Smyth I. Gillies S. Georgas K. Wainwright B. Chenevix-Trench G. Wicking C. Hum Mut 2000;16(1):43-8 Medline 20334495 Hedgehog signaling in animal development and human disease. [Review]Bailey EC. Scott MP. Johnson RL Ernst Schering Research Foundation Workshop. 2000;(29):211-35 Medline 20399009 Hedgehog signalling in cancer. (Review)Toftgård R. Cell Mol Life Sci 2000;(57):1720-1731 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

BiblioGene - INIST Contributor(s)Written 05- Jean-Loup Huret


1997 Updated 01-


Updated 12-2000 Erika Lindström, Rune Toftgård

CitationThis paper should be referenced as such : Huret JL . PTCH1. Atlas Genet Cytogenet Oncol Haematol. May 1997 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PTCH100.html Huret JL . PTCH1. Atlas Genet Cytogenet Oncol Haematol. January 1999 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PTCH100.html Lindstrom E, Toftgård R . PTCH1. Atlas Genet Cytogenet Oncol Haematol. December 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/PTCH100.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



TFF2 (TreFoil Factor 2)

IdentityOther names SP (Spasmolytic Polypeptide)

Hugo TFF2 Location 21q22.3 belongs to the TFF cluster

DNA/RNADescription 5.1 kb gene, 4 exons Transcription 600 bp

Protein Description precursor: 129 amino acids; mature peptide: 106 amino acids; 3-

dimentional structure was solved; the129 amino acids TFF2 protein contains a signal peptide; the mature secreted peptide of 106 amino acids contains two TFF (TreFoil Factor) domains and one acidic C-terminal domain

Expression under normal condition, TFF2 is expressed in mucus neck cells of the fundus, basal cells of the antral and pyloric glands and by the Brunner's glands of the duodenum

Localisation secreted in gastric fluid Function in repair and epithelial restitution of the gastro-intestinal mucosa Homology TFF2 belongs to the Trefoil peptide Family (TFF) and possesses two

tandemly duplicated TFF motifs each being homologous to the TFF motif of TFF1 and TFF3. The TFF motif spans about 40 amino acids and is formed by 6 conserved residues involved in specific disulfides bridges

Implicated inEntity TFF2 was found implicated in inflamatory bowel diseases, cancers of

gastrointestinal organs such as stomach and pancreas; in constrast to TFF1 and TFF3, TFF2 expression was not found in breast carcinomas


Hugo TFF2


GDB TFF2 Entrez_Gene TFF2 7032 trefoil factor 2 (spasmolytic protein 1)

Cards Atlas TFF2ID264 GeneCards TFF2 Ensembl TFF2 CancerGene TFF2 Genatlas TFF2 GeneLynx TFF2 eGenome TFF2 euGene 7032


GoldenPath TFF2 - 21q22.3 chr21:42639538-42644176 - 21q22.3 (hg17-May_2004)

Ensembl TFF2 - 21q22.3 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM]

HomoloGene TFF2 Gene and transcription

Genbank AB038162 [ SRS ] AB038162 [ ENTREZ ] Genbank U47292 [ SRS ] U47292 [ ENTREZ ] Genbank BC032820 [ SRS ] BC032820 [ ENTREZ ] Genbank BM817851 [ SRS ] BM817851 [ ENTREZ ] Genbank BM853946 [ SRS ] BM853946 [ ENTREZ ] RefSeq NM_005423 [ SRS ] NM_005423 [ ENTREZ ] RefSeq NT_086913 [ SRS ] NT_086913 [ ENTREZ ] AceView TFF2 AceView - NCBI TRASER TFF2 Traser - Stanford Unigene Hs.2979 [ SRS ] Hs.2979 [ NCBI ] HS2979 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt Q03403 [ SRS] Q03403 [ EXPASY ] Q03403 [ INTERPRO ] Prosite PS00025 P_TREFOIL [ SRS ] PS00025 P_TREFOIL [ Expasy ] Interpro IPR000519 P_trefoil [ SRS ] IPR000519 P_trefoil [ EBI ] CluSTr Q03403

Pfam PF00088 Trefoil [ SRS ] PF00088 Trefoil [ Sanger ] pfam00088 [ NCBI-CDD ]

Smart SM00018 PD [EMBL]



OMIM 182590 [ map ]

GENECLINICS 182590

SNP TFF2 [dbSNP-NCBI]

SNP NM_005423 [SNP-NCI] SNP TFF2 [GeneSNPs - Utah] TFF2 [SNP - CSHL] TFF2] [HGBASE - SRS]

General knowledge Family Browser TFF2 [UCSC Family Browser]

SOURCE NM_005423

SMD Hs.2979 SAGE Hs.2979 Amigo process|defense response

Amigo process|digestion

PubGene TFF2 Other databases Probes

Probe TFF2 Related clones (RZPD - Berlin)


BibliographyThe amino acid sequence of pancreatic spasmolytic polypeptide.Thim L, Thomsen J, Christensen M, Jorgensen KH. Biochim Biophys Acta 1985; 827: 410-418. Breast cancer-associated pS2 protein: synthesis and secretion by normal stomach mucosa.Rio MC, Bellocq JP, Daniel JY, Tomasetto C, Lathe R, Chenard MP, Batzenschlager A, Chambon P.


Science 1988; 241: 705-708. A new family of growth factor-like peptides. 'Trefoil' disulphide loop structures as a common feature in breast cancer associated peptide (pS2), pancreatic spasmolytic polypeptide (PSP), and frog skin peptides (spasmolysins).Thim L. FEBS Lett 1989; 250: 85-90. hSP, the domain-duplicated homolog of pS2 protein, is co-expressed with pS2 in stomach but not in breast carcinoma.Tomasetto C, Rio MC, Gautier C, Wolf C, Hareuveni M, Chambon P, Lathe R. EMBO J 1990; 9: 407-414. Induction of pS2 and hSP genes as markers of mucosal ulceration of the digestive tract.Rio MC, Chenard MP, Wolf C, Marcellin L, Tomasetto C, Lathe R, Bellocq JP, Chambon P. Gastroenterology 1991; 100: 375-379. Expression of the breast cancer associated gene pS2 and the pancreatic spasmolytic polypeptide gene (hSP) in diffuse type of stomach carcinoma.Theisinger B, Welter C, Seitz G, Rio MC, Lathe R, Chambon P, Blin N. Eur J Cancer 1991; 27: 770-773. Association of the human spasmolytic polypeptide and an estrogen-induced breast cancer protein (pS2) with human pancreatic carcinoma.Welter C, Theisinger B, Seitz G, Tomasetto C, Rio MC, Chambon P, Blin N. Lab Invest 1992; 66: 187-192. Pancreatic spasmolytic polypeptide: first three-dimensional structure of a member of the mammalian trefoil family of peptides.Gajhede M, Petersen TN, Henriksen A, Petersen JF, Dauter Z, Wilson KS, Thim L. Structure 1993;1: 253-262. The mouse one P-domain (pS2) and two P-domain (mSP) genes exhibit distinct patterns of expression.Lefebvre O, Wolf C, Kedinger M, Chenard MP, Tomasetto C, Chambon P, Rio MC. J Cell Biol 1993; 122: 191-198. Trefoil peptide gene expression in gastrointestinal epithelial cells in inflammatory bowel disease.Wright NA, Poulsom R, Stamp G, Van Noorden S, Sarraf C, Elia G, Ahnen D, Jeffery R, Longcroft J, Pike C, et al. Gastroenterology 1993; 104: 12-20. Human spasmolytic polypeptide is a cytoprotective agent that stimulates cell


migration.Playford RJ, Marchbank T, Chinery R, Evison R, Pignatelli M, Boulton RA, Thim L, Hanby AM. Gastroenterology 1995; 108: 108-116. Oral trefoil peptides protect against ethanol- and indomethacin-induced gastric injury in rats.Babyatsky MW, de Beaumont M, Thim L, Podolsky DK. Gastroenterology 1996; 110: 489-497. The three human trefoil genes TFF1, TFF2, and TFF3 are located within a region of 55 kb on chromosome 21q22.3.Seib T, Blin N, Hilgert K, Seifert M, Theisinger B, Engel M, Dooley S, Zang KD, Welter C. Genomics 1997; 40: 200-202. REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed


2000 Catherine Tomasetto

CitationThis paper should be referenced as such : Tomasetto C . TFF2 (TreFoil Factor 2). Atlas Genet Cytogenet Oncol Haematol. December 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/TFF2ID264.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



FGFR1OP (FGFR1 oncogene partner)

IdentityOther names FOP (Fibroblast Growth Factor Receptor 1 Oncogene Partner)

Hugo FGFR1OP Location 6q27

FOP (6q27) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.


DNA/RNADescription full length cDNA: 1 627 bp Transcription a single open reading frame of 1 197 bp mRNA; putative ATG: bp 85;

stop codon at bp 1 282; alternative splicing: multiple FOP transcript variants resulting from exon 7 or exon 11 splices

Protein


Description 399 amino acids; predicted molecular mass: 44.3 kDa; Hydrophobic

protein containing in its N- and C-termini several regions folding in a-helices with leucine-rich repeats with the consensus sequence L-X2-L-X3-5-L-X3-5-L, in one-third of which the leucine is substituted by either a valine or an isoleucine

Expression ubiquitous expression Localisation cell cytoplasm Function unknown

Implicated inEntity t(6;8)(q27; p12) myeloproliferative disorder --> FOP - FGFR1 ; stem-cell

myeloproliferative disorder associated with the 8p12 chromosomal translocations with fusions to the catalytic domain of FGFR1

Disease stem-cell myeloproliferative disorder characterized by myeloid hyperplasia, T -cell lymphoblastic leukemia/lymphoma and peripheral blood eosinophilia, and it generally progresses to acute myeloid leukemia; specific to the 8p12 chromosomal region.

Prognosis very poor (median survival: 12 mths) Cytogenetics additional abnormalities: 2q+ and +21 Hybrid/Mutated Gene 5' FOP - 3' FGFR1; localisation: der(6)

Abnormal Protein

N-term leucine-rich region from FOP fused to the catalytic domain of FGFR1 (FGFR1 intracellular region minus the major part of the juxtamembrane domain)


Oncogenesis constitutive kinase activity of FGFR1 through constitutive activation of FGFR1

signal transduction pathways via putative constitutive dimerization capability mediated by the FOP N-term LRR sequences


Hugo FGFR1OP GDB FGFR1OP Entrez_Gene FGFR1OP 11116 FGFR1 oncogene partner

Cards GeneCards FGFR1OP Ensembl FGFR1OP Genatlas FGFR1OP GeneLynx FGFR1OP eGenome FGFR1OP euGene 11116


GoldenPath FGFR1OP - 6q27 chr6:167383227-167424476 + 6q27 (hg17-May_2004)

Ensembl FGFR1OP - 6q27 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM]


HomoloGene FGFR1OP Gene and transcription

Genbank Z94721 [ SRS ] Z94721 [ ENTREZ ] Genbank AJ420472 [ SRS ] AJ420472 [ ENTREZ ] Genbank BC011902 [ SRS ] BC011902 [ ENTREZ ] Genbank BC037785 [ SRS ] BC037785 [ ENTREZ ] Genbank BU625682 [ SRS ] BU625682 [ ENTREZ ] RefSeq NM_007045 [ SRS ] NM_007045 [ ENTREZ ] RefSeq NM_194429 [ SRS ] NM_194429 [ ENTREZ ] RefSeq NT_086699 [ SRS ] NT_086699 [ ENTREZ ] AceView FGFR1OP AceView - NCBI TRASER FGFR1OP Traser - Stanford Unigene Hs.487175 [ SRS ] Hs.487175 [ NCBI ] HS487175 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt O95684 [ SRS] O95684 [ EXPASY ] O95684 [ INTERPRO ] Prosite PS50896 LISH [ SRS ] PS50896 LISH [ Expasy ] Interpro IPR006594 LisH [ SRS ] IPR006594 LisH [ EBI ] CluSTr O95684 Smart SM00667 LisH [EMBL] Blocks O95684

Polymorphism : SNP, mutations, diseases OMIM 605392 [ map ] GENECLINICS 605392 SNP FGFR1OP [dbSNP-NCBI] SNP NM_007045 [SNP-NCI] SNP NM_194429 [SNP-NCI] SNP FGFR1OP [GeneSNPs - Utah] FGFR1OP [SNP - CSHL] FGFR1OP] [HGBASE - SRS]

General knowledge Family Browser FGFR1OP [UCSC Family Browser]

SOURCE NM_007045 SOURCE NM_194429 SMD Hs.487175 SAGE Hs.487175 Amigo process|positive regulation of cell proliferation PubGene FGFR1OP



Probe Cancer Cytogenetics (Bari) Probe FGFR1OP Related clones (RZPD - Berlin)


BibliographyThe t(6;8)(q27;p11) translocation in a stem cell myeloproliferative disorder fuses a novel gene, FOP, to fibroblast growth factor receptor 1.Popovici C, Zhang B, Grégoire MJ, Jonveaux P, Lafage-Pochitaloff M, Birnbaum D, Pébusque MJ. Blood 1999; 93: 1381-1389. REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed


2001 Marie-Joséphe Pébusque

CitationThis paper should be referenced as such : Pébusque MJ . FGFR1OP (FGFR1 oncogene partner). Atlas Genet Cytogenet Oncol Haematol. January 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/FOPID140.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



MST1R (Macrophage stimulating 1 receptor)

IdentityOther names C-MET-related tyrosine kinase (RON)

RON protein tyrosine kinase (RON); Macrophage stimulating protein receptor (MSP-receptor) Hugo MST1R Location 3p21.31 between LIMD1 and CCXCR1; between D3S1568 and D3S3822

DNA/RNA

Description Twenty coding exons. All exons are small in size, ranging from 93 bp to 253 bp, with

the exception of exon 1 (>1 kb). Exon 1, 2 and 3 code for the SEMA domain of the RON protein (red). Exons 4 codes for a PSI domain (orange), a modular structure about 50 amino acid long containing eight conserved Cys residues, putatively involved in protein-protein interactions. The sequence between exon 4 and 12 codes for four repeated modular structures called IPT (yellow); these domains are found in cell surface receptors such as MET and RON as well as in intracellular transcription factors where they are involved in DNA binding. Part of exon 12 codes for the transmembrane domain, (pink). Exons 14 to 20 codes for the kinase domain (blue).Four-digit numbers refer to splice sites location, based on RON cDNA sequence

Transcription Two major transcripts are detected, respectively 4.5 kb and 2 kb. ORF: 4204 bp

Protein


Description The RON protein is a glycosilated heterodimeric protein composed of

one a- (35 kD) and one b-chain (150 kD) linked by an unknown number of disulfide bonds. The two chains derive from a single-chain precursor of about 185 kD that undergoes proteolytic cleavage at the basic amino acid site KRRRR. The a-chain is extracellular. The b-chain has an extracellular part, a one-pass transmembrane helix and an intracellular part containing the tyrosine kinase domain. The first 24 amino acids made the putative signal peptide (green). The SEMA domain (consisting of most of a- and part of b- chain) contains the ligand (MSP) binding pocket (unpublished data). Tyrosine residues 1238 and 1239 (upward arrowheads in the figure) are essential for up-regulation of RON catalytic activity. Tyrosine residues1353 and 1360 (downward arrowheads, in the figure) make a docking site that mediates high affinity interactions with multiple SH2-containing signal transducers

Expression RON is expressed in human keratinocytes (it was initially cloned from a keratinocytes cDNA library). By Northern blot was found expressed in the following normal human tissues: skin, lung, bone marrow, small intestin, heart, pancreas, thyroid, prostate, testis (unpublished data), colonic mucosa and in a variety of cell types: granulocytes and monocytes, hematopoietic cells such as erythroid and myeloid progenitor cells, macrophages, osteoclasts, bone marrow megakaryocytes, epithelial and neuroendocrine cells

Localisation Transmembrane protein. Function The ligand for RON is MSP. Originally, MSP was described as a serum

factor enhancing the chemotactic response of murine peritoneal macrophage to the C5a fraction of complement, but RON/MSP complex has a much broader spectrum of activity. Ligand-stimulated RON activates the pathways regulating cell adhesion and motility, growth and survival. STK (the mouse ortholog) is essential for peri-implantation development during gestation, as STK-deficient mice (STK-/-) are viable only through the blastocyst stage. Hemizygous mice (STK+/-) grow to adulthood; however, they are highly susceptible to endotoxic shock and appear to be compromised in their ability to down-regulate nitric oxide production. These results suggest STK has a limiting role not only in the inflammatory response but also in early mouse development

Homology RON belongs to the MET receptor tyrosine kinase (RTK) family. On the basis of the presence of multiple PSI domains and a SEMA domain, it has been proposed that plexins, MET RTK family and VESPR (virus-encoded semaphorin receptor) are classified as semaphorins. RON orthologs have been identified in mouse (STK), chicken (c-sea) and


Xenopus

MutationsGerminal Several Single Nucleotide Polymorphisms (SNPs) were found in healthy

CEPH individuals: A993G :Gln322Arg (index of heterozygosity: 0.28); C4024T (same-sense variant, index of heterozygosity: 0.03); A4031G: Arg1344Gly (index of heterozygosity: 0.46)

Somatic T915C: Leu296Pro was found in the tumor DNA of one single patient affected with adenocarcinoma of the lung. The mutated protein is not constitutively activated. The mutation has no causative role in the disease. Experimental introduction in the RON kinase domain of amino acid substitutions D1232V and M1254T - initially found in the oncogenes KIT, RET and MET, involved respectively in mastocytosis, Multiple Endocrine Neoplasia type 2B and renal papillary carcinoma - results in activation of oncogenic capacity and triggers a strong metastatic activity of RON. Expression of these RON mutants causes cellular accumulation of b-catenin via inhibition of its association with the axin/GSK complex and subsequent protection from proteasomal degradation (Danilkovitch-Miagkova, personal communication).

Implicated inEntity RON was found over-expressed in infiltrating breast carcinomas. A

constitutively activated splicing variant of RON (lacking exon 11) was found in the gastric carcinoma cell line KATO-III. This variant induces activation of cell dissociation, motility and invasion of extracellular matrices. The same variant was found in malignant colonic mucosa. Another splicing variant, lacking exons 5 and 6, was found in the human colon carcinoma cell line HT-29.Truncated STK - the mouse RON ortholog - confers susceptibility to Friend virus-induced erythroleukemia in mice, and c-sea, the avian ortholog, causes erythroblastosis in chickens.


Hugo MST1R GDB MST1R

Entrez_Gene MST1R 4486 macrophage stimulating 1 receptor (c-met-related tyrosine kinase)

Cards Atlas RONID287 GeneCards MST1R Ensembl MST1R CancerGene MST1R Genatlas MST1R GeneLynx MST1R


eGenome MST1R euGene 4486


GoldenPath MST1R - 3p21.31 chr3:49899442-49916074 - 3p21.31 (hg17-May_2004)

Ensembl MST1R - 3p21.31 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene MST1R

Gene and transcription Genbank X70040 [ SRS ] X70040 [ ENTREZ ] RefSeq NM_002447 [ SRS ] NM_002447 [ ENTREZ ] RefSeq NT_086638 [ SRS ] NT_086638 [ ENTREZ ] AceView MST1R AceView - NCBI TRASER MST1R Traser - Stanford Unigene Hs.517973 [ SRS ] Hs.517973 [ NCBI ] HS517973 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt Q04912 [ SRS] Q04912 [ EXPASY ] Q04912 [ INTERPRO ]

Prosite PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 PROTEIN_KINASE_ATP [ Expasy ]

Prosite PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 PROTEIN_KINASE_DOM [ Expasy ]

Prosite PS00109 PROTEIN_KINASE_TYR [ SRS ] PS00109 PROTEIN_KINASE_TYR [ Expasy ]

Prosite PS51004 SEMA [ SRS ] PS51004 SEMA [ Expasy ] Interpro IPR002909 IPT/TIG_recept [ SRS ] IPR002909 IPT/TIG_recept [ EBI ] Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ] Interpro IPR002165 Plexin_repeat [ SRS ] IPR002165 Plexin_repeat [ EBI ] Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ] Interpro IPR001627 Sema [ SRS ] IPR001627 Sema [ EBI ] Interpro IPR001245 Tyr_pkinase [ SRS ] IPR001245 Tyr_pkinase [ EBI ] Interpro IPR008266 Tyr_pkinase_AS [ SRS ] IPR008266 Tyr_pkinase_AS [ EBI ]

CluSTr Q04912

Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI-CDD ]

Pfam PF01437 PSI [ SRS ] PF01437 PSI [ Sanger ] pfam01437 [ NCBI-CDD ] Pfam PF01403 Sema [ SRS ] PF01403 Sema [ Sanger ] pfam01403 [ NCBI-CDD ]

Pfam PF01833 TIG [ SRS ] PF01833 TIG [ Sanger ] pfam01833 [ NCBI-CDD ] Prodom PD000001 Prot_kinase[INRA-Toulouse]


Prodom Q04912 RON_HUMAN [ Domain structure ] Q04912 RON_HUMAN [ sequences sharing at least 1 domain ]


OMIM 600168 [ map ] GENECLINICS 600168 SNP MST1R [dbSNP-NCBI] SNP NM_002447 [SNP-NCI] SNP MST1R [GeneSNPs - Utah] MST1R [SNP - CSHL] MST1R] [HGBASE - SRS]

General knowledge Family Browser MST1R [UCSC Family Browser]

SOURCE NM_002447 SMD Hs.517973 SAGE Hs.517973

Enzyme 2.7.1.112 [ Enzyme-SRS ] 2.7.1.112 [ Brenda-SRS ] 2.7.1.112 [ KEGG

] 2.7.1.112 [ WIT ] Amigo function|ATP binding Amigo process|cell motility Amigo process|defense response Amigo process|fertilization (sensu Metazoa) Amigo component|integral to plasma membrane Amigo function|macrophage colony stimulating factor receptor activity Amigo process|positive regulation of cell proliferation Amigo process|protein amino acid phosphorylation Amigo function|protein-tyrosine kinase activity Amigo function|receptor activity Amigo process|signal transduction Amigo function|transferase activity BIOCARTA Msp/Ron Receptor Signaling Pathway PubGene MST1R


Probe MST1R Related clones (RZPD - Berlin) PubMed


BibliographyA serum protein that stimulates macrophage movement, chemotaxis and spreading.


Leonard EJ, Skeel A. Exp Cell Res. 1976; 102: 434-8. The v-sea oncogene of avian erythroblastosis retrovirus S13: another member of the protein-tyrosine kinase gene family.Smith DR, Vogt PK, Hayman MJ. Proc Natl Acad Sci U S A. 1989; 86: 5291-5. Centre d'Žtude du polymorphisme humain (CEPH): collaborative genetic mapping of the human genome.Dausset J, Cann H, Cohen D, Lathrop M, Lalouel JM, White R. Genomics 1990; 6: 575-577. A novel putative receptor protein tyrosine kinase of the MET family.Ronsin C, Muscatelli F, Mattei MG, Breathnach R. Oncogene 1993; 8: 1195-1202. RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP.Gaudino G, Follenzi A, Naldini L, Collesi C, Santoro M, Gallo KA, Godowski PJ, Comoglio PM. EMBO J. 1994;13: 3524-32. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Hoppener JW, van Amstel HK, Romeo G, et al. Nature 1994; 367: 375-376. Molecular cloning of a novel receptor tyrosine kinase gene, STK, derived from enriched hematopoietic stem cells.Iwama A, Okano K, Sudo T, Matsuda Y, Suda T. Blood. 1994; 83: 3160-9. Action and target cell specificity of human macrophage-stimulating protein (MSP).Skeel A, Leonard EJ. J. Immunol 1994; 152: 4618-4623. Identification of the ron gene product as the receptor for the human macrophage stimulating protein.Wang MH, Ronsin C, Gesnel MC, Coupey L, Skeel A, Leonard EJ, Breathnach R. Science. 1994; 266: 117-9. The proto-oncogene RON is involved in development of epithelial, bone and neuro-endocrine tissues.


Gaudino G, Avantaggiato V, Follenzi A, Acampora D, Simeone A, Comoglio PM. Oncogene 1995; 11: 2627-2637. Terminal differentiation of murine resident peritoneal macrophages is characterized by expression of the STK protein tyrosine kinase, a receptor for macrophage-stimulating protein.Iwama A, Wang MH, Yamaguchi N, Ohno N, Okano K, Sudo T, Takeya M, Gervais F, Morissette C, Leonard EJ, et al. Blood. 1995; 86: 3394-403. Modulation of megakaryocytopoiesis by human macrophage-stimulating protein, the ligand for the RON receptor.Banu N, Price DJ, London R, Deng B, Mark M, Godowski PJ, Avraham H. J Immunol. 1996;156: 2933-40. A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype.Collesi C, Santoro MM, Gaudino G, Comoglio PM. Mol Cell Biol 1996; 16: 5518-5526. Macrophage-stimulating protein activates STK receptor tyrosine kinase on osteoclasts and facilitates bone resorption by osteoclast-like cells.Kurihara N, Iwama A, Tatsumi J, Ikeda K, Suda T. Blood. 1996; 87: 3704-10. The tyrosine kinase receptors RON and SEA control "scattering" and morphogenesis of liver progenitor cells in vitro.Medico E, Mongiovi AM, Huff J, Jelinek MA, Follenzi A, Gaudino G, Parsons JT, Comoglio PM. Mol Biol Cell 1996; 7: 495-504. Cloning and expression of Xenopus HGF-like protein (HLP) and Ron/HLP receptor implicate their involvement in early neural development.Nakamura T, Aoki S, Takahashi T, Matsumoto K, Kiyohara T, Nakamura T. Biochem Biophys Res Commun. 1996; 224(2): 564-73. Role of c-kit receptor tyrosine kinase in the development, survival and neoplastic transformation of mast cells.Tsujimura T. Pathol Int. 1996; 46: 933-8. Review. Macrophage-stimulating protein induces proliferation and migration of murine keratinocytes.Wang MH, Dlugosz AA, Sun Y, Suda T, Skeel A, Leonard EJ. Exp Cell Res. 1996; 226: 39-46.


Requirement of phosphatidylinositol-3 kinase for epithelial cell migration activated by human macrophage stimulating protein.Wang MH, Montero-Julian FA, Dauny I, Leonard EJ. Oncogene 1996; 13: 2167-2175. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas.Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Zbar B, et al. Nat Genet 1997; 16: 68-73. Overexpression of the RON gene in human breast carcinoma.Maggiora P, Marchio S, Stella MC, Giai M, Belfiore A, De Bortoli M, Di Renzo MF, Costantino A, Sismondi P, Comoglio PM. Oncogene 1998; 16: 2927-2933. Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the RON receptor.Santoro MM, Penengo L, Minetto M, Orecchia S, Cilli M, Gaudino G. Oncogene 1998; 17: 741-749. Characterization of the mouse RON/Stk receptor tyrosine kinase gene.Waltz SE, Toms CL, McDowell SA, Clay LA, Muraoka RS, Air EL, Sun WY, Thomas MB, Degen SJ. Oncogene 1998; 16: 27-42. Macrophage-stimulating protein and its receptor in non-small-cell lung tumors: induction of receptor tyrosine phosphorylation and cell migration.Willett CG, Wang MH, Emanuel RL, Graham SA, Smith DI, Shridhar V, Sugarbaker DJ, Sunday ME. Am J Respir Cell Mol Biol. 1998; 18: 489-96. Domains in plexins: links to integrins and transcription factors.Bork P, Doerks T, Springer TA, Snel B. Trends Biochem Sci 1999; 24: 261-263. Macrophage simulating protein-induced epithelial cell adhesion is mediated by a PI3-K-dependent, but FAK-independent mechanism.Danilkovitch A, Skeel A, Leonard EJ. Exp. Cell Res. 1999; 248:575-582. The Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse.Muraoka RS, Sun WY, Colbert MC, Waltz SE, Witte DP, Degen JL, Friezner Degen SJ.


J Clin Invest. 1999; 103: 1277-85. Presence of RON receptor tyrosine kinase and its splicing variant in malignant and non-malignant human colonic mucosa.Okino T, Egami H, Ohmachi H, Takai E, Tamori Y, Nakagawa K, Nakano S, Akagi J, Sakamoto O, Suda T, Ogawa M. Int J Oncol. 1999; 15: 709-14. Fv2 encodes a truncated form of the Stk receptor tyrosine kinase.Persons DA, Paulson RF, Loyd MR, Herley MT, Bodner SM, Bernstein A, Correll PH, Ney PA Nat Genet 1999; 23: 159-165. Chicken macrophage stimulating protein is a ligand of the receptor protein-tyrosine kinase Sea.Wahl RC, Hsu RY, Huff JL, Jelinek MA, Chen K, Courchesne P, Patterson SD, Parsons JT, Welcher AA. J Biol Chem. 1999; 274: 26361-8. Gene structure of the human receptor tyrosine kinase RON and mutation analysis in lung cancer samples.Angeloni D, Danilkovitch-Miagkova A, Ivanov SV, Breathnach R, Johnson BE, Leonard EJ, Lerman MI. Genes Chromosomes Cancer. 2000; 29:147-56. Overexpression and activation of the RON receptor tyrosine kinase in a panel of human colorectal carcinoma cell lines.Chen YQ, Zhou YQ, Angeloni D, Kurtz AL, Qiang XZ, Wang MH. Exp Cell Res. 2000; 261: 229-38. Two independent signaling pathways mediate the antiapoptotic action of macrophage-stimulating protein on epithelial cells.Danilkovitch A, Donley S, Skeel A, Leonard EJ. Mol. Cell Biol. 2000; 20: 2218-2227. REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed


2001 Debora Angeloni, Michael I. Lerman

CitationThis paper should be referenced as such : Angeloni D, Lerman MI . MST1R (Macrophage stimulating 1 receptor). Atlas Genet


Cytogenet Oncol Haematol. January 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/RONID287.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



FIM (fused in myeloproliferative disorders). (updated: old version not available)

IdentityOther names ZNF198 (zinc finger protein 198).

RAMP Hugo FIM Location 13q12 proximal from FLT1 and FLT3

FIM (13q12) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.


DNA/RNADescription full length cDNA: 5,016 bp; a single open reading frame of 4,137 bp;

alternative spliced cDNA variant Transcription main transcripts: 5.0 and 7.5 kb

Protein


Description 1 379 amino acids; hydrophobic protein containing several motifs: a N-

terminal cystein-rich region containing ten repeats with the consensus sequence C-X2-C-X18-24-F/Y-C-X3-C, which correspond to a novel zinc finger motifs, a highly hydrophobic proline-rich stretch, and a bipartite nuclear localization signal

Expression wide Localisation cell nucleus and nucleolus; within the nucleolus, colocalizes with UBF

(Upstream Binding Factor) Function may be involved in the regulation of rRNA transcription Homology FIM is related to DXS6673E, a gene which may be related with mental

retardation

Implicated inEntity t(8;13)(p12;q12)/ANLL-NHL --> 5' FIM - 3' FGFR1 ; stem-cell

myeloproliferative disorder associated with the 8p12 chromosomal translocations; fused to the catalytic domain of FGFR1

Disease stem-cell myeloproliferative disorder characterized by myeloid hyperplasia, T -cell lymphoblastic leukemia/lymphoma and peripheral blood eosinophilia, and it generally progresses to acute myeloid leukemia; specific to the 8p12 chromosomal region

Prognosis very poor (median survival: 12 mths) Cytogenetics usually, t(8;13)(p12;q12) occurs as a single anomaly; duplication of the

der(13) was found during disease progression, suggesting that the crucial event might lie on this derivative chromosome; additional abnormalities:+8, +21


Hybrid/Mutated Gene 5' FIM - 3' FGFR1; localisation: der(13)

Abnormal Protein

aberrant tyrosine kinase composed of the N-term two-thirds of FIM (retaining the 10 putative zinc finger motifs), and the FGFR1 intracellular region minus the major part of the juxtamembrane domain

Oncogenesis constitutive kinase activity of FGFR1 through constitutive activation of FGFR1 signal transduction pathways via constitutive dimerization capability mediated by the FIM N-term zinc finger sequences


Hugo FIM GDB ZNF198 Entrez_Gene ZNF198 7750 zinc finger protein 198

Cards Atlas ZNF198ID114 GeneCards ZNF198 Ensembl ZNF198 CancerGene ZNF198 Genatlas ZNF198 GeneLynx ZNF198 eGenome ZNF198 euGene 7750


GoldenPath ZNF198 - 13q12 chr13:19430810-19558939 + 13q12.11 (hg17-May_2004)


Ensembl ZNF198 - 13q12.11 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene ZNF198

Gene and transcription Genbank AJ007676 [ SRS ] AJ007676 [ ENTREZ ] Genbank AL137119 [ SRS ] AL137119 [ ENTREZ ] Genbank AL138688 [ SRS ] AL138688 [ ENTREZ ] Genbank AF012126 [ SRS ] AF012126 [ ENTREZ ] Genbank AF035374 [ SRS ] AF035374 [ ENTREZ ] RefSeq NM_003453 [ SRS ] NM_003453 [ ENTREZ ] RefSeq NM_197968 [ SRS ] NM_197968 [ ENTREZ ] RefSeq NT_086801 [ SRS ] NT_086801 [ ENTREZ ] AceView ZNF198 AceView - NCBI TRASER ZNF198 Traser - Stanford Unigene Hs.507433 [ SRS ] Hs.507433 [ NCBI ] HS507433 [ spliceNest ]

Protein : pattern, domain, 3D structure SwissProt Q9UBW7 [ SRS] Q9UBW7 [ EXPASY ] Q9UBW7 [ INTERPRO ] Interpro IPR011017 TRASH [ SRS ] IPR011017 TRASH [ EBI ] Interpro IPR010507 ZF-MYM [ SRS ] IPR010507 ZF-MYM [ EBI ] CluSTr Q9UBW7

Pfam PF06467 zf-MYM [ SRS ] PF06467 zf-MYM [ Sanger ] pfam06467 [ NCBI-CDD ]

Smart SM00746 TRASH [EMBL] Blocks Q9UBW7

Polymorphism : SNP, mutations, diseases OMIM 602221 [ map ] GENECLINICS 602221 SNP ZNF198 [dbSNP-NCBI] SNP NM_003453 [SNP-NCI] SNP NM_197968 [SNP-NCI] SNP ZNF198 [GeneSNPs - Utah] ZNF198 [SNP - CSHL] ZNF198] [HGBASE - SRS]

General knowledge Family Browser ZNF198 [UCSC Family Browser]

SOURCE NM_003453 SOURCE NM_197968 SMD Hs.507433 SAGE Hs.507433


Amigo component|nucleus Amigo process|regulation of transcription, DNA-dependent Amigo function|zinc ion binding PubGene ZNF198


Probe Cancer Cytogenetics (Bari) Probe FIM Related clones (RZPD - Berlin)


BibliographyFibroblast growth factor receptor 1 is fused to FIM in stem-cell myeloproliferative disorder with t(8;13).Popovici C, Adelaide J, Ollendorff V, Chaffanet M, Guasch G, Jacrot M, Leroux D, Birnbaum D, Pebusque MJ Proc Natl Acad Sci U S A 1998 May 12;95(10):5712-7 Medline 98245146

The t(8;13)(p11;q11-12) rearrangement associated with an atypical myeloproliferative disorder fuses the fibroblast growth factor receptor 1 gene to a novel gene RAMP.

Nat Genet 1998 Jan;18(1):84-7

Smedley D, Hamoudi R, Clark J, Warren W, Abdul-Rauf M, Somers G, Venter D, Fagan K, Cooper C, Shipley J. Hum Mol Genet 1998 Apr;7(4):637-42

FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syndrome.Xiao S, Nalabolu SR, Aster JC, Ma J, Abruzzo L, Jaffe ES, Stone R, Weissman SM, Hudson TJ, Fletcher JA

Medline 98085877

Characterization of FIM-FGFR1, the fusion product of the myeloproliferative disorder-associated t(8;13) translocation.

Ollendorff V, Guasch G, Isnardon D, Galindo R, Birnbaum D, Pébusque MJ. J Biol Chem 1999 Sep 17;274(38):26922-30. ZNF198-FGFR1 transforming activity depends on a novel proline-rich ZNF198 oligomerization domain.Xiao S, McCarthy JG, Aster JC, Fletcher J. Blood 2000 Jul 15;96(2):699-704 REVIEW articles automatic search in PubMed Last year automatic search in PubMed


publications BiblioGene - INIST Contributor(s)Written 03-

1998 Jean-Loup Huret, Dominique Leroux

Updated 01-2001 Marie-Joséphe Pébusque

CitationThis paper should be referenced as such : Huret JL, Leroux D . FIM (fused in myeloproliferative disorders).. Atlas Genet Cytogenet Oncol Haematol. March 1998 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ZNF198ID114.html Pébusque MJ . FIM (fused in myeloproliferative disorders).. Atlas Genet Cytogenet Oncol Haematol. January 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Genes/ZNF198ID114.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



t(1;3)(p36;q21) (updated: old version not available)

Identity

t(1;3)(p36;q21) G-banding (left) - Courtesy Diane H. Norback, Eric B. Johnson, and

Sara Morrison-Delap, Cytogenetics at the Waisman Center; R-banding (right) Courtesy Pascale Cornillet-Lefebvre and StŽphanie Struski (above) and Christiane Charrin (below)

Clinics and PathologyDisease Myeloid lineage (MDS, ANLL, therapy related ANLL, CML, MPD);

features similar to those of the 3q21q26 syndrome including normal or elevated platelet count at diagnosis, megakaryocytic hyperplasia and dysplasia. Very rarely in lymphoid lineage

Phenotype / cell stem origin

of 39 cases, there were: 22 myelodysplastic syndromes (MDS) (17/22 transformed into refractory acute non lymphoblastic leukemia (ANLL) of -M1 or -M4 type), 8 de novo ANLL, 3 therapy-related MDS, 2 polycythemia vera, 1 essential thrombocythemia, 1 chronic myelogenous leukemia (CML), 1 multiple myeloma, 1 waldenstrom's macroglobulinemia

Epidemiology patients are aged: 30-80 yrs Clinics Roughly 50% of patients present with MDS, another 10% with therapy

associated MDS, 25% with de novo AML, and the remainder with a range of other myeloproliferative disorders. The majority of MDS patients transform into AML with a short preleukemic phase. Blood data: frequent thrombocytosis or normal platelet count


Cytology frequently characterized by dysmegakaryocytopoiesis Pathology The pathology is typical of MDS, often with a prominent monocytic

component. Trilineage dysplasia. Acute leukemias that evolve usually show the morphology of M4 AML.

Treatment Patients are treated with conventional chemotherapy for AML. Prognosis Very poor so far: from 16 cases, median survival was 6 mths in ANLL,

20 mths in MDS

CytogeneticsNote Other rearrangements showing similar clinical features include

inv(3)(q21q26), t(3;3)(q21;q26), t(3;5)(q21;q31), t(3;8)(q21;q24), and t(3;21)(q26;q22). The breakpoints in 3q21 cluster in a 50 kb region centromeric to the breakpoint in inv(3)(q21;q26) and the ribophorin gene (RPN1). The breakpoints at 1p36 are clustered in a 90 kb region at 1p36.3.

Additional anomalies del (5q) in 5 of 20 cases (1/4)

Genes involved and ProteinsNote Mechanisms of Oncogenesis : The available data suggest that

transcription of MEL1 (MDS1/EVI1 -like gene) is activated as a result of translocation bringing the gene just 3Õ to RPN1 gene at 3q21. MEL1 is a 1257 amino acid protein that is homologous (63% similar in amino acid sequence) to EVI. The mechanism of activation of MEL1 is similar to EVI1 that is activated by juxtaposition 3Õ to RPN1 in the t(3;3)(q21;q26) and 5Õ to RPN1 in the inv(3)(q2126). It appears that MEL1 is normally expressed in uterus and kidney and not in normal hematopoietic cells or in leukemias that lack the t(1;3)(p36;q31 The MEL1 protein contains 2 DNA binding domains (7 C2H2 zinc finger repeats at the amino terminus and 3 zinc finger repeats at the carboxyl terminus). The amino terminal domain of MEL1 contains a PRD domain, a motif also found in the same location in the MDS1/EV1 protein but not in MDS1). This is of interest because this domain is also found in RIZ, PRDI-BF1, and egl-43 and is homologous to the SET (Suvar3-9, Enhancer of zeste, Trithorax) domain that present in MLL. Inclusion of this domain in EVI1 appears to convert EVI1 from a transcriptional repressor to an activator. Therefore MEL1 may be a transcriptional activator. The target genes of MEL1 have not been identified.

External linksOther database t(1;3)(p36;q21) Mitelman database (CGAP - NCBI)

Other database t(1;3)(p36;q21) CancerChromosomes (NCBI)

Bibliography


A new translocation , t(1;3)(p36;q21), in myelodysplastic disorders.Moir DJ, Jones PA, Pearson J, Duncan JR, Cook P, Buckle VJ. Blood 1984; 64: 553-555. Medline 6743828 Rearrangements of chromosome 3 involving bands 3q21 and 3q26 are associated with normal or elevated platelet counts in acute non-lymphocytic leukemia.Bittner MA, Neilly ME, Le Beau MM, Pearson MG, Rowley JD. Blood 1985; 66: 1362-1370. Medline 4063525

t(1;3)(p36;q21) in acute nonlymphocytic leukemia: a new cytogenetic-clinicopathologic association.

Medline 4063527

Bloomfield CD, Garson OM, Volin L, Knuutilia S, de la Chapelle A. Blood 1985; 66: 1409-1413.

Welborn JL, Lewis JP, Jenks H, Walling P

Diagnostic and prognostic significance of t(1;3)(p36;q21) in the disorders of hematopoiesis.

Cancer Genet Cytogenet. 1987; 28: 277-285. Medline 87301329

Cancer Genetics Cytogenetics 1992; 64: 80-85.

Acute leukemia with t(1;3)(p36;q21), evolution to t(1;3)(p36;q21) , t(14;17)(q32;q21) and loss of red cell A and Le(b) antigens.Marsden KA, Pearse AM, Collins GG, Ford DS, Heard S, Kimber RI.

Medline 1458454

Clinical, haematological and cytogenetic features in 24 patients with structural rearrangements of the Q arm of chromosome 3.

Medline 93168610

Grigg AP, Gascoyne RD, Phillips GL, Horsman DE Br J Haematol. 1993; 83: 158-165.

Secker-Walker LM, Mehta A, Brain B.

Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom cancer cytogenetic group study.

Br J Haematol. 1995; 91: 490-501. Medline 96027684 The PR domain of the Rb-binding zinc finger protein RIZ1 is a protein binding interface and is related to the SET domain functioning in chromatin mediated gene expression.Huang S, Shao G, Limin L.


J Biological Chem 1998; 273: 15933-15939. Medline 9632640

A novel gene MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells.

Medline 11050005

Mochizuki N, Shimizu S, Nagasawa T, Tanaka H, Taniwaki M, Yokota J, Morishita K.Blood 2000; 96: 3209-3214.

Shimizu S, Suzukawa K, Kodera T, Nagasawa T, Abe T, Taniwaki M, Yagasaki F, Tanaka H, Fujisawa S, Johansson B, Ahlgren T, Yokota J, Morishita K.

Identification of breakpoint cluster regions at 1p36.3 and 3q21 in hematologic malignancies with t(1;3)(p36;q21).

Genes Chromosom Cancer 2000; 27: 229-238. Medline 20146274 Contributor(s)Written 08-


Updated

Jay L Hess

11-2000 Pascale Cornillet-Lefebvre, Sylvie Daliphard, Stéphanie Struski

Updated 05-2002

CitationThis paper should be referenced as such : Huret JL . t(1;3)(p36;q21). Atlas Genet Cytogenet Oncol Haematol. August 1997 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0103.html Cornillet-Lefebvre P, Daliphard S, Struski S . t(1;3)(p36;q21). Atlas Genet Cytogenet Oncol Haematol. November 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0103.html Hess JL . t(1;3)(p36;q21). Atlas Genet Cytogenet Oncol Haematol. May 2002 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t0103.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



del(17p) in non-Hodgkin's lymphoma (NHL)

Identitythe 17p- chromosome is a secondary change in most cases of NHL Note

Clinics and PathologyDisease virtually all histologic subsets of NHL may harbour a 17p- chromosome;

there is variation in the reported incidence due to heterogeneity of histologic classification and to the different sensitivity of the detection methods � 10 to 15% of follicle centre cell lymphoma (FCCL) and mantle cell lymphomas (MCL) may carry a 17p- chromosome; minority of marginal zone B-cell lymphomas may be associated with 17p deletion � this anomaly is rarely found in T-cell NHL

Prognosis the 17p- chromosome was reported to predict for a poor prognosis in low grade lymphomas; any abnormality of chromosome 17 was also reported to negatively affect survival in lymphomas of all histologic grades

CytogeneticsCytogenetics Morphological

� the deleted segment may vary in size and many cases with sub-microscopic deletions involving the 17p13 band were reported by FISH; cases with unbalanced 17p translocations leading to 17p loss were also described; these cases may be associated with dicentric rearrangements � the 17p- is usually associated with transformation of a low-grade FCCL with t(14;18) into a high grade lymphoma; likewise, there is a higher incidence of 17p- in the blastoid variant of MCL with t(11,14) than in the typical form the deletion may be detected by G or R-banding; FISH using a 17p13/p53 probe is recommended, this technique being more sensitive than conventional cytogenetics

Cytogenetics Molecular

Genes involved and ProteinsNote the majority of cases with 17p- carry a p53 gene deletion, associated

with mutation of the remaining allele; there may be a small fraction of cases with a more distal deletion involving an as yet unidentified locus

External links


del(17p) in non-Hodgkin's lymphoma (NHL)

Mitelman database (CGAP - NCBI)

Other database

BibliographyRefractoriness to chemotherapy and poor survival related to abnormalities of chromosomes 17 and 7 in lymphoma.Cabanillas F, Pathak S, Grant G, Hagermeister FB, McLaughlin P, Swan F, Rodriguez MA, Trujillo J, Cork A, Butler JJ, Katz R, Bourne S, Freireich EJ. Am J Med 1989; 87: 167-173.

Leukemia 1998; 12: 510-516.

Beˆ S, Ribas M, Hernˆndez J M, Bosch F, Pinyol M, Hernˆndez L, Garc“a J L, Flores T, Gonzˆles M, L˜pez-Guillermo A, Piris MA, Cardesa A, Montserrat E, Mir˜ R, Campo E.

Translocations involving the short arm of chromosome 17 in chronic B-lymphoid disorders: frequent occurence of dicentric rearrangement and possible association with adverse outcome.

Cytogenetic findings in peripheral T-cell lymphomas as a basis for distinguishing low-grade and high-grade lymphomas.Schlegelberger B, Himmler A, Godde E, Grote W, Feller AC, Lennert K. Blood 1994; 83: 505-511. Prognostic value of chromosomal abnormalities in follicular lymphoma.Tilly H, Rossi A, Stamatoullas A, Lenormand B, Bigorgne C, Kunlin A, Monconduit M, Bastard C. Blood 1994; 84: 1043-1049. Analysis of p53 gene deletions in patients with non-HodgkinÕs lymphoma by dual-colour fluorescence in-situ hybridization.Clodi K, Younes A, Goodacre A, et al. Br J Haematol 1997; 98: 913-921. Identification of a commonly deleted region at 17p13.3 in leukemia and lymphoma associated with a 17p abnormality.Sankar M, Tanaba K, Kumaravel TS, Arif M, Shintani T, Yagi S, Kyo T, Dohy H, Kamada N.

Increased number of chromosomal imbalances and high-level DNA amplifications in mantle cell lymphoma are associated with blastoid variants.

Blood; 1999; 93: 4365-4374.

Callet-Bauchu E, Salles G, Gazzo S, Poncet C, Morel D, Pag�s J, Coiffier B, Coeur P, Felman P. Leukemia 1999; 13: 460-468. Cytogenetic profile of lymphoma of follicle mantle lineage: correlation with clinicobiological features.


Cuneo A, Bigoni R, Rigolin G M, Roberti M G, Bardi A, Piva N, Milani R, Bullrich F, Veronese ML, Croce C, Birg F, Dohner H, Hagemeijer A, Castoldi GL. Blood 1999; 93: 1372-1380. Molecular cytogenetic characterization of marginal zone B-cell lymphoma: correlation with clinicopathologic findings in 14 cases.Cuneo A, Bigoni R, Roberti MG, Milani R, Agostini P, Cavazzini F, Minotto C, De Angeli C, Bardi A, Negrini M, Cavazzini P, Castoldi G. Haematologica 2001; 86: 75-81. Contributor(s)

12-2000 Antonio Cuneo, Gianluigi Castoldi Written

CitationThis paper should be referenced as such : Cuneo A and Castoldi G . del(17p) in non-Hodgkin's lymphoma (NHL). Atlas Genet Cytogenet Oncol Haematol. December 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/del17pNHLID2083.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



del(20q) in myeloid malignancies

Identity

del(20q) G- banding (left) - Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap Cytogenetics at theWaisman Center; R-banding (right) - top: Courtesy Jean-Luc Lai; bottom: Editor

Clinics and Pathology

a very large spectrum of hematological malignancies as myelodysplastic syndromes (MDS), acute non lymphocytic leukemias (ANLL), polycythemia vera, chronic neutrophilic leukemia as described in various types of hematological disorders, 20q- appears as a primary karyotypic abnormality occurring in a pluripotential hematopoietic stem cell; the pathogenic mechanism by which 20q- alters the hematopoietic stem cells in hematological disorders remains unknown; 20q- may confer a proliferative advantage to myeloid cells through deletion of a tumor suppressor gene

an interstitial or terminal deletion of the long arm of chromosome 20 (20q-) has been described as the second most frequent sole clonal structural abnormality (5 %) behind t(9.22)

Disease


Epidemiology

� in MDS, 20q- alone is associated with a good prognosis regarding survival and potential for AML evolution, as defined by the International Prognostic Scoring System (IPSS) for MDS prognosis

Prognosis

� in de novo acute leukemia, a poor response to treatment and a reduced survival is observed � in myeloproliferative disorders, the presence of 20q does not appear to adversely affect survival

CytogeneticsCytogenetics the breakpoint on chromosome 20 is not constant; 20q- is frequently


Morphological associated with other cytogenetic abnormalities as del(5q), trisomy 8, trisomy 21, deletions or translocations involving the long arm of chromosome 13; a newly described translocation t(11;20)(p15;q11) resulting in a NUP98- TOP1 fusion gene was described in therapy-related myelodysplastic syndrome (RAEB); t(11;20)(p15;q11) is a rare recurrent translocation reported in patients with MDS, ANLL and polycythemia vera

Cytogenetics Molecular Additional anomalies

a small fragment (around 8 Mb), proximally flanked by D20S206 and distally by D20S119 and UT 654 was identified using FISH del(5q), trisomy 8, deletions or translocations involving 13q and trisomy 21

Genes involved and ProteinsNote genes remaining within this deleted region are topoisomerase 1 (TPO1-

OMIN 126420), phospholipase C (PLC1), hepatocyte factor nuclear 4 (HNF4) and adenosine desaminase (ADA); recently, a new gene KRML transcriptional regulator was mapped in the smallest commonly deleted region in malignant myeloid leukemias

External linksOther database del(20q) in myeloid malignancies Mitelman database (CGAP - NCBI)

BibliographyReport of the committee on chromosome changes in neoplasia.Mitelman F, Kaneko Y, Trent J.

The prognostic significance of deletion of the long arm of chromosome 20 in myeloid disorders.

Blood 1997; 89: 2079-2088.

Genes Chromosom Cancer 1998; 21: 75-81.

Cytogenetic Cell Genet 1991; 58: 1053-1079.

Campbell LJ, Garson OM. Leukemia 1994; 8: 67-71.

Kurtin PJ, Dewald GW, Shields DJ et al. Hemopathology 1996; 106: 680-688.

International scoring system for evaluating prognosis in myelodysplastic syndromes.Greenberg P, Cox C, Le Beau MM, et al,

Wang P, Innantuoni K, Davis EM et al.

The t(11;20)(p15;q11) chromosomal translocation associated with therapy-


related myelodysplastic syndrome results in an NUP98-TOP1 fusion.Ahuja HG, Felix CA, Aplan PD.

Human KRML (MAFB): cDNA cloning, genomic structure, and evaluation as candidate tumor suppressor gene in myeloid leukemias.

Blood 1999; 94: 3258-3261.

Wang PW et al. Genomics 1999; 59: 275-281


2000 Chrystèle Bilhou-Nabera

CitationThis paper should be referenced as such : Bilhou-Nabera C. . del(20q) in myeloid malignancies. Atlas Genet Cytogenet Oncol Haematol. December 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/del20qID1040.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



Juvenile Chronic Myelogenous Leukemia (JCML)

IdentityNote the proper terminology of this disorder is controversial; many authors,

including the European Working Group on MDS in Childhood favor the term JMML; another working group suggests using the term JMML syndrome with a qualifier with or without monosomy 7 or 7q-

Juvenile myelomonocytic leukemia (JMML) Other names Juvenile myelomonocytic leukemia syndrome (JMML syndrome)

Clinics and PathologyDisease JCML is a chronic myeloproliferative disorder that typically affects

young children: more than 95% of cases are diagnosed before age 4 Phenotype / cell stem origin

evidence exists for leukemic involvement of CD34-positive stem cells and monocyte-macrophage, erythroid, and B-lymphoid lineages in cases with cytogenetic abnormalities

Epidemiology annual incidence is estimated to be roughly 4/million; median age 1-4 yrs; sex ratio: 1.4M/1F

Clinics

� proposed clinical criteria from the International Juvenile Myelomonocytic Leukemia Working Group includes: 1. white blood cell count > 13 x 109/L (corrected for nucleated red blood cells) 2. absolute monocyte count > 1 x 109/L (corrected) 3. presence of immature myeloid precursors (myelocytes, promyelocytes, and myeloblasts) in the peripheral blood 4. bone marrow aspirate revealing < 30% blasts 5. no Ph chromosome on cytogenetic assessment

� splenomegaly, lymphadenopathy, and skin rash are common; typical peripheral blood findings include leukocytosis (usually less than 100 x 109/L), monocytosis, and thrombocytosis with variable degree of left shift; myeloblasts average about 5% of total nucleated cells; elevation of fetal hemoglobin (hbF) very common; absence of the Philadelphia chromosome in all cases

� about 15% of cases are associated with neurofibromatosis type 1 ( NF-1 mutation)

Pathology � blood: leukocytosis, monocytosis, left shift in myeloid maturation, circulating mucleated red blood cells � bone marrow: hypercellular marrow with mildly increased M:E ratio (typically 5:1), dispersed erythroid elements, and decreased numbers of megakaryocytes; dyplasia is usually not prominent


Treatment intensive chemotherapy and all trans retinoic have not been shown to induce durable remissions; complete remissions have been achieved with stem cell transplantation

Prognosis the disease is uniformly fatal when treated with conventional chemotherapy; among those who undergo bone marrow transplantations, the majority ultimately relapse, with an overall survival rate of 25%


other than the frequent association with monosomy 7, no consistent cytogenetic abnormalities have been identified; whether the infantile monosomy 7 syndrome is distinct from JCML is controversial

Genes involved and ProteinsNote mechanisms of Oncogenesis:

JCML patients show spontaneous growth of granulocyte-macrophage colony forming units (CFU-GM) from peripheral blood, which appears to be the result of hypersensitivity to GM-CSF, IL-3, or SCF; cases associated with NF-1 are likely to be the result of constitutive activation of the Ras pathway as a result of decreased GT Pase activity although there is also evidence of a GAP independent function; up to 30% of cases show mutations in K-ras and N-ras; the importance of the RAS pathway has been confirmed in mouse models with targeted disrupted of Nf-1; recently data suggest that TNFa produced by neoplastic cells may prevent expansion of hematopoietic progenitors

BibliographyLoss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells.Bollag G, Clapp DW, Shih S, Adler F, Zhang YY, Thompson P, Lange BJ, Freedman MH, McCormick F, Jacks T, Shannon K. Nat Genet 1996; 12: 144-148. Medline 96154185 Juvenile Chronic Mylogenous Leukemia.Hess JL, Zutter MM, Castleberry RP, Emanuel PD. Am J Clin Path 1996; 105: 238-248. Medline 96187727 Nf1 deficiency causes Ras-mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia.Largaespada DA, Brannan CI, Jenkins NA, Copeland NG. Nature Genetics 1996; 12: 137-143. Medline 96154184 Juvenile myelomonocytic leukemia: analyses of tratment results in the EORTC


Children's Leukemia Cooperative Group (CLCG).Lutz P, Zix-Kieffer I, Souillet G, Bertrand Y, Dhooge C, Rubie C, Mazingue F, Marguerite F, Machinuad-Lacroix F, Rialland X, Plouvier E, Behar C, Vilmer E, Philippe N, Otten J. Bone Marrow Transplantation 1996; 18: 1111-1116. Medline 97126465 Loss of heterozygosity of NF1 gene in juvenile chronic myuelogenous leukemia with neurofibromatosis type 1.Kai S, Sumita H, Fujioka K, Takahashi H, Hanzawa N, Funabiki T, Ikuta K, Sasaki H.Int J Hematol 1998; 68: 53-60. Medline 98378790 Nf1 regulates hematopoietic progenitor cell growth and ras signaling in response to multiple cytokines.Zhang YY, Vik TA, Ryder JW, Srour EF, Jacks T, Shannon K, Clapp DW. J Exp Med 1998; 187: 1893-1902. Medline 98270918 Myelodysplastic snydrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7.Hasle H., Arico M, Basso G, Biondi A, Rajnoldi AC, Creutzig U, Fenu S, Fonatsch C, Haas OA, Harbott J, Kardos G, Kerndrup G, Mann G, Niemeyer CM, Ptoszkova H, Ritter J, Slater R, Stary J, Stollmann-Gibbels B, Testi AM, van Wering ER, Zimmerman M. Leukemia 1999; 13: 376-385. Medline 99184532 Alternative donor bone marrow transplantation for children with juvenile myelomonocytic leukemia.Bunin N, Saunders F, Leahey A, Doyle J, Calderwood S, Freedman MH. J Ped Hematol Oncol 1999; 21: 461-463. Medline 20065717 Nf1 and GM-CSF interact in myeloid leukemogenesis.Birnbaum RA, O'Marcaigh A, Wardak Z, Zhang YY, Dranoff G, Jacks T, Clapp DW, Shannon KM. Molecular Cell 2000; 5: 189-195. Medline 20142671 Evidence that juvenile myelomonocytic leukemia can arise from a pluripotential stem cell.Cooper LJ, Shannon KM, Loken MR, Weaver M, Stephens K, Sievers EL. Blood 2000; 96: 2310-2313. Medline 20435367


Myelodysplastic syndromes in children. A critical review of the clinical manifestations and mangement.Novitzky N. Am J Hematol 2000; 63: 212-222. Medline 20170720 Contributor(s)

12-2000 Jay L. Hess Written

CitationThis paper should be referenced as such : Hess JL . Juvenile Chronic Myelogenous Leukemia (JCML). Atlas Genet Cytogenet Oncol Haematol. December 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/JCMLID1099.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



t(6;8)(q27;p12)

Clinics and PathologyDisease

median survival: 6 months

multilineage disorder with combined occurrence of myeloid malignancy and T- cell NHL, or myeloid metaplasia


the same t(6;8)(q27;p12) is found both in the bone marrow and in the lymph node: the multilineage involvement suggests the malignant transformation of a primitive hematopoietic stem cell

Epidemiology 4 cases are described; median age 29 yrs (range 23-48); sex ratio: 2M/2F

Clinics aggressive disease; complex picture of myeloid hyperplasia progressing to myelodysplasia and T- lymphoma, and acute non lymphocytic leukemia ; enlarged lymph node infiltrated by myeloid blast cells; blood data: high WBC (median 40 X 109/l); myelemia; monocytosis and eosinophilia

Evolution CR is obtained, but is promptly followed by relapse progressing rapidly to acute non lymphocytic leukemia

Prognosis

CytogeneticsCytogenetics Morphological occurs as a single anomaly


mega YAC 959-A -4 (1260kb) from CEPH; FGFR1-specific cosmid 134.8

Genes involved and ProteinsGene Name FGFR1

FOP (FGFR1 Oncogene Partner)

Location 8p12 Protein FGF receptor with tyrosine kinase activity Gene Name

Location hydrophobic protein containing a-helices in the N- and C-termini with leucine-rich repeats.

6q27 Protein

Result of the


chromosomal anomalyHybrid gene

Description

FR1 signal transduction pathways,

via putative dimerization of the fusion protein via the FOP leucine-rich repeats

breakpoint in FGFR1 intron 8 which encodes the juxtamembrane domain, breakpoint in FOP intron 6

Fusion Protein Description

aberrant tyrosine kinase composed of the putative leucine-rich N-terminal region of FOP, and the FGFR1 intracellular region minus the major part of the juxtamembrane domain

Oncogenesis through constitutive activation of FG

External linksOther database t(6;8)(q27;p12) Mitelman database (CGAP - NCBI)

Other database t(6;8)(q27;p12) CancerChromosomes (NCBI)

To be noted Additional cases are needed to delineate the epidemiology of this rare

entity: you are welcome to submit a paper to our new Case Report section.

Bibliography


Simultaneous occurrence of a T-cell lymphoma and a chronic myelogenous leukemia with an unusual karyotype.Vannier JP, Bizet M, Bastard C, Bernard A, Ducastelle T, Tron P. Leukemia Res 1984; 8: 647-657.

Elsner S, Martin H, Rode C, Wassman B, Ganser A, Hoelzer D. Br J Haematol, 1994; 87: 124.

MacDonald D, Aguiar RC, Mason PJ, Goldman JM, Cross NC.

t(6;8), t(8;9) and t(8;13) translocations associated with stem cell myeloproliferative disorders have close or identical breakpoints in chromosome region 8p11-12.

Blood, 1999; 93: 1381-1389.

An uncommon chromosomal translocation t(6;8) associated with atypical myelogenous leukemia/myeloproliferative disease detected by fluorescence in situ hybridisation.

A new myeloproliferative disorder associated with chromosomal translocations involving 8p11: a review.

Leukemia 1995; 9: 1628-1630.

Chaffanet M, Popovici C, Leroux D, Jacrot M, Adélaide J, Dastugue N, Grégoire MJ, Hagemeijer A, Lafage-Pochitaloff M, Birnbaum D, Pébusque MJ. Oncogene 1998; 16: 945-949.

The t(6;8)(q27;p11) translocation in a stem cell myeloproliferative disorder fuses a novel gene, FOP, to fibroblast growth factor receptor 1.Popovici C, Zhang B, Gregoire MJ, Jonveaux P, Lafage-Pochitaloff M, Birnbaum D, Pébusque MJ.


2000 Marie-Josèphe Pébusque

CitationThis paper should be referenced as such :

Pébusque MJ . t(6;8)(q27;p12). Atlas Genet Cytogenet Oncol Haematol. December 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t68ID1090.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology



t(8;13)(p12;q12) (updated: old version not available)

Clinics and PathologyDisease a myeloproliferative disorder that is frequently associated with T cell, or

less commonly, B-cell non Hodgkin lymphoma Phenotype / cell stem origin

may involve a stem cell involving both myeloid, T lineage, and B-cell lineage

Epidemiology

14 cases are described; median age 43 yrs (range 18-68); sex ratio: 6M/8F

Clinics aggressive disease; complex picture of myeloid hyperplasia progressing to myelodysplasia and Tor -B- cell lymphoma; enlarged lymph node; blood data: high WBC (median 40 X 109/l); myelemia; monocytosis and eosinophilia

Evolution the disease transforms to ANLL, or occasionally ALL, in a median of 6 months

Prognosis median survival: 12 months


the same t(8;13) is found both in the bone marrow and in the lymph node, ruling out the hypothesis of a leukemoid reaction caused by a lymphoma; the multilineage involvement suggests the malignant transformation of a primitive hematopoietic stem cell.

Probes megac Yacs 770-c-2 (1390 kb) and 959-a-4 (1260kb), 856-b-6, 967; 899e2 - (CEPH); BAC 7M15; PAC RPCI 20-G12; FGFR1-specific cosmid 134.8;

Additional anomalies

usually occurs as a single anomaly; duplication of the der(13) was found during disease progression, suggesting that the crucial event might lie on this derivative chromosome; +8, +21 are also recurrently found

Genes involved and ProteinsGene Name FGFR1

Location 8p12 Gene Name ZNF198 (also called FIM or ID_P)


Location 13q12 Protein zinc finger protein (ten repeats in the N-terminal region with the

consensus sequence C-X2-C-X18-24-(F/Y)-C-X3-C that corresponds to a novel type of zing finger motifs), a hydrophobic repeat (proline-rich), and potentially two putative nuclear localisation signals

Result of the chromosomal anomalyHybrid gene

Description breakpoint in FGFR1 intron 8 Fusion Protein Description

Aberrant tyrosine kinase composed of the N-term two-thirds of FIM (retaining the 10 putative zinc finger motifs), and the FGFR1 intracellular region minus the major part of the juxtamembrane domain (and deleting the N-term immunoglobulin-like and central transmembrane domains of FGFR1)

Oncogenesis through constitutive activation of FGFR1 signal transduction pathways, possibly via dimerization capability mediated by the FIM N-term sequences of the fusion protein

External linksOther database t(8;13)(p12;q12) Mitelman database (CGAP - NCBI)

Other database t(8;13)(p12;q12) CancerChromosomes (NCBI)


entity: you are welcome to submit a paper to our new Case Report


section.

BibliographyAbnormalities of chromosome band 8p11 in leukemia: two clinical syndromes can be distinguished on the basis of MOZ involvement.Aguiar RC, Chase A, Coulthard S, Macdonald DH, Carapeti M, Reiter A, Sohal J, Lennard A, Goldman JM, Cross NC Blood. 1997; 90: 3130-3135. Medline 98025897 Fibroblast growth factor receptor 1 is fused to FIM in stem-cell myeloproliferative disorder with t(8;13).Popovici C, Adelaide J, Ollendorff V, Chaffanet M, Guasch G, Jacrot M, Leroux D, Birnbaum D, Pebusque MJ Proc Natl Acad Sci U S A. 1998; 95: 5712-5717. Medline 98245146

Reiter A, Sohal J, Kulkarni S, Chase A, Macdonald DHC, Aguiar RCT, Gon¡alves C, Hernandez JM, Jennings B, Goldman JM, Cross NCP.

Consistent fusion of ZNF198 to the fibroblast growth factor receptor-1 in the t(8;13)(p11;q12) myeloproliferative syndrome.

Blood 1998; 92: 1735-1742. The t(8;13)(p11;q11-12) rearrangement associated with an atypical myeloproliferative disorder fuses the fibroblast growth factor receptor 1 gene to a novel gene RAMP.Smedley D, Hamoudi R, Clark J, Warren W, Abdul-Rauf M, Somers G, Venter D, Fagan K, Cooper C, Shipley J. Hum Mol Genet 1998; 7: 637-642. FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syndrome.Xiao S, Nalabolu SR, Aster JC, Ma J, Abruzzo L, Jaffe ES, Stone R, Weissman SM, Hudson TJ, Fletcher JA. Nat Genet 1998 ;18: 84-87. Genomic structure of ZNF198 and location of breakpoints in the t(8;13)(p11;q12) myeloproliferative syndrome.Kulkarni S, Reiter A, Smedley D, Goldman JM, Cross NCP. Genomics 1999; 55: 118-121. Characterization of FIM-FGFR1, the fusion product of the myeloproliferative disorder-associated t(8;13) translocation.Ollendorff V, Guasch G, Isnardon D, Galindo R, Birnbaum D, Pebusque MJ. J Biol Chem 1999; 274: 26922-26930. ZNF198-FGFR1 transforms Ba/F3 cells to factor independence and results in


high level tyrosine phosphorylation of STAT 1 and STAT 5.Smedley D, Demiroglu A, Abdul-Rauf M, Heath C, Cooper C, Shipley J, Cross NCP. Neoplasia 1999; 1: 349-355. ZNF198-FGFR1 transforming activity depends on a novel proline-rich ZNF198 oligomerization domain.Xiao S, McCarthy JG, Aster JC, Fletcher J. Blood 2000; 96: 699-704. Contributor(s)Written 03-

1998 Jean-Loup Huret, Dominique Leroux and Alain Bernheim

Updated 12-2000 Marie-Josèphe Pébusque, and Nicholas CP Cross

CitationThis paper should be referenced as such : Huret JL, Leroux D, Bernheim A . t(8;13)(p12;q12). Atlas Genet Cytogenet Oncol Haematol. March 1998 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t813ID1094.html Pébusque MJ, Cross NCP . t(8;13)(p12;q12). Atlas Genet Cytogenet Oncol Haematol. December 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t813ID1094.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



t(9;12)(q34;p13)

Clinics and PathologyDisease described in only 6 cases; acute lymphoblastic leukemia (ALL), acute

non lymphocytic leukemia (ANLL) and chronic myeloid leukemia (CML) Prognosis numbers small, but one CML case had allogeneic BMT and is in

complete remission, the remaining cases had rapid disease progression and died of shortly after diagnosis

CytogeneticsCytogenetics Morphological t(9;12)(q34;p13), cryptic at the cytogenetic level

Variants t(9;12;14)(q34;p13;q22) and complex insertions of ETV6 into ABL

Genes involved and ProteinsGene Name ABL

ETV6 is fused to exon 2 of ABL in the three cases described tyrosine kinase, localized primarily to the nucleus

ETV6

Location 9q34 Dna / Rna Protein Gene Name

12p13 9 exons; alternate splicing contains Helix-Loop-Helix (HLH) at N-terminal end and ETS DNA binding domain at C-terminal end; wide expression; nuclear localization; ETS- related transcription factor

Location Dna / Rna Protein

Result of the chromosomal anomalyHybrid gene Description

5Õ ETV6 - 3Õ ABL; two different fusion breakpoints have been described; ETV6 exon 4 fused in frame to ABL exon 2 (Type A) and ETV6 exon 5 fused in frame to ABL exon 2 (Type B); ETV6 maintains the HLH domain and ABL the tyrosine kinase domain


Fusion Protein Description Oncogenesis � the HLH domain of ETV6 induces oligomerization, which results in

the constitutive activation of the kinase domain of ABL; this is thought to result in phosphorylation of JAK2

a 155 kDa protein in Type A, 180 kDa protein in Type B; has elevated tyrosine kinase activity, localized in the cytoplasm and co-localizes with the actin filaments of the cells

and activation of the ONCOGENESIS � biological activity very similar to BCR-ABL

External linksOther database t(9;12)(q34;p13) Mitelman database (CGAP - NCBI)

t(9;12)(q34;p13)Other database CancerChromosomes (NCBI)



BibliographyThe novel activation of ABL by fusion to an ets-related gene TEL.Papadopoulos P, Ridge SA, Boucher CA, Stocking C, Wiedemann LM. Cancer Res 1995; 55: 34-38. Medline 9513529 Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia.Golub TR, Goga A, Barker GF, Afar DEH, McLaughlin J, Bohlander SK, Rowley JD, Witte WN, Gilliland DG. Molec Cell Biol 1996; 16: 4107-4116. Medline 96315635 BCR/ABL-negative chronic myeloid leukemia with ETV6/ABL fusion.Andreasson P, Johansson B, Carlsson M, Jarlsfelt I, Fioretos T, Mitelman F, Hšglund M. Genes Chromosom Cancer 1997; 20: 299-304. Medline 98032542

Br J Haematol 1998; 102: 475-485.

Haemopoietic transformation by the TEL/ABL oncogene.Hannemann JR, McManus DM, Kabarowski JHS, Wiedemann LM.

Medline 98359133 Bcr/Abl activates transcription of the Bcl-0X gene through STAT5.


Gesbert F, Griffin JD. Blood 2000; 96: 2269-2276. Medline 20435360

Blood 2000; 95; 2076-2083.

Transforming properties of chimeric TEL-JAK proteins in Ba/F3 cells.Lacronique V, Boureaux A, Monni R, Dumon S, MauchauffŽ M, Mayeux P, Gouilleux F, Berger R, Gisselbrecht S, Ghysdael J, Bernard OA.

Medline 20173576

Molecular cytogenetic and clinical findings in ETV6/ABL1-positive leukemia.

Van Limbergen H, Beverloo HB, van Drunen E, Janssens A, HŠhlen K, Poppe B, Van Roy N, Marynen P, De Paepe A, Slater R, Speleman F. Genes Chromosom Cancer 2001; Published Online: 20 Dec 2000

Contributor(s)12-2000

Written Nyla A. Heerema

CitationThis paper should be referenced as such : Heerema NA . t(9;12)(q34;p13). Atlas Genet Cytogenet Oncol Haematol. December 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t912ID1080.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



11q23 rearrangements in leukaemia (updated: old version not available)

Clinics and PathologyDisease de novo and therapy related leukaemias; acute non lymphocytic

leukaemia (ANLL) and acute lymphocytic leukaemia (ALL) grossly represent half cases each; myelodysplasia (MDS) in the remaining 5%; biphenotypic leukaemia at times (likely to be more frequent with more investigations); 11q23 rearrangements in treatment related leukaemias (5-10% of 11q23 cases) are found mainly following a treatment with anti-topoisomerase II, or an intercalating topoisomerase II inhibitor, but also after alkylating agents treatment and/or radiotherapy; the prior cancer is variable.

Epidemiology


ANLL: M5a in half cases, M4 (20%), M1 or M5b (10% each), M2 (5%); ALL: B-cell mostly, L1 or L2, CD19+ in 60% of B-ALL cases, CD10+ 35%; T-ALL in rare cases (<1%); MDS: most often RA or RAEB1T. 25% are infant (<1 yr) cases; children and adults each represent 50% of cases; M/F = 0.9 (NS) See also 11q23 rearrangements in childhood acute lymphoblastic leukemia: Clinical aspects and congenital leukemias

Clinics organomegaly; frequent CNS involvement (5%); high WBC (> 50 X 109/l in 40%).


Molecular studies have identified a human homologue of the drosophila trithorax gene (designed HRX or MLL). MLL is a developmental regulator and is structurally altered in leukemia associated translocations that show an abnormality at band 11q23. The MLL gene on 11q23 is involved in a number of translocations with different partner chromosomes. The most common translocations observed in childhood AML are the t(9;11)(p21;q23) and the t(11;19)(q23;p13.1); other translocations of 11q23 involve at least 30 different partners chromosomes. Molecular studies have shown that MLL is rearranged more frequently than is revealed by conventional cytogenetic studies. A partial tandem duplication of MLL gene has also been reported in the majority of adult patients whose leukemic blast cells have a +11 and in some with normal karyotype. There is a strong association between AML M5/M4 and deletion and translocations involving 11q23. Sometimes cases of 11q23 M5B and M4, and occasionally M2 or M1 also show MLL rearrangement. Two clinical subgroups of patients have a high frequency of 11q23 aberration and M5 subtypes: one is AML in infants with MLL rearrangement in about 50% of cases; the other group is "secondary leukemia" (sAML) potentially after treatment with DNA topoisomerase II inhibitors. In general the translocations in these leukemia are the same as those occurring in "de novo" leukemia i.e. t(9;11), t(11;19) - Courtesy Georges Flandrin, CD-ROM AML/MDS G. Flandrin/ICG. TRIBVN

Prognosis very poor in general; variable according to the translocation, the phenotype, the age , and whether the leukaemia is de novo or treatment related.


� I- the most frequent are: � normal karyotype: a partial tandem duplication (in situ) of MLL is present in a percentage of ANLL with a normal karyotype; LARG, in 11q23, has been found fused to MLL � +11 : 1% of ANLL and MDS as well; M1, M2, and M4 ANLL;


therapy related ANLL; MDS evolving towards ANLL; partial tandem duplication (in situ) of MLL; visible dup(11q) also occur. � t(4;11)(q21;q23) : represent 1/3 of cases; found mainly (95%) in B-ALL (CD19+ in 75%, CD10+ in 15%); treatment related ALL in 5%; unbalanced sex ratio < 4 yrs (1M/2F); children represent half cases (infants (<1 yr) accounting for 1/3 of all cases); children aged 2-9 yrs appear to have a much better prognosis; the gene involved in 4q21 is AF4, a transcription activator. � t(6;11)(q27;q23) : 5% of cases; mostly; children and young adults; male predominance; the gene involved in 6q27 is AF6; role in signal transduction. � t(9;11)((p23;q23) : represent 1/4 of cases; found in ANLL mainly in M5a (70%), or M4 (10%); in ALL in 10%; de novo and therapy related AL; children represent half cases (infants (<1 yr) accounting for 15% of all cases); the gene involved in 9p22 is AF9, a transcription activator. � t(10;11)(p12;q23) : 5% of cases; M4 or M5 ANLL; ALL at times; from infants and children to (rare) adult cases; the gene involved in 10p12 is AF10, a transcription activator. � t(11;19)(q23;p13.1) : 5% of cases; M4 or M5 ANLL most often; de novo and therapy related AL; adults mainly; the gene involved in 19p13.1 is ELL, a transcription activator. � t(11;19)(q23;p13.3) : 5% of cases; ALL, biphenotypic AL and ANLL (M4/M5 mainly); therapy related AL; T-cell ALL at times, these T-cell cases are the only cases of t(11;19) with an excellent prognosis, a rather rare feature in this page!!; mostly found in infants (half cases), and other children (altogether: 70%), or young adults (cases > 40 yrs are 4%; 23 unpublished cases and a review of 90 cases); the gene involved in 19p13.3 is ENL, a transcription activator. � II- Various other11q23 rearrangements have be described; these are rare, some are even poorly known, but the ones listed below are recurrent and/or with ascertainement of a partner gene to MLL: � inv(11)(p15q23) : ANLL and MDS. � del(11q): one case (t-ANLL) showed involvement of GAS7, a gene sitting in 17p13; del(11q) with MLL rearrangement is likely to be heterogeneous, as MLL shows multiple possible partners, and, not rarely, complex translocations. � t(X;11)(q13;q23) : ANLL; the gene involved in Xq13 is AFX1, a transcription regulator. � t(X;11)(q22;q23); the gene in Xq22 is Septin2 � t(1;11)(p32;q23) : ALL and ANLL; the gene involved in 1p32 is AF1P. � t(1;11)(q21;q23) : mostly M4 ANLL; the gene involved in 1q21 is AF1q. � t(2;11)(p21;q23) : ANLL and MDS; may be found associated with del(5q) � t(2;11)(q11;q23) the gene in 2q11 is LAF4 � t(3;11)(p21;q23) : the gene involved in 3p21 is AF3p21 � t(3;11)(q25;q23); the gene in 3q25 is GMPS � t(5;11)(q31;q23), and ins(5;11)(q31;q13q23); the latter involve


AF5q31 in 5q31; very rare � t(5;11)(q31;q23) the gene in 5q31 is GRAF � t(6;11)(q21;q23): ANLL; the gene in 6q21 is AF6q21, a transcription regulator � t(9;11)(q34;q23) the gene in 9q34 is AF9q34 � t(10;11)(p11.2;q23); the gene in 10p11.2 is ABI1 � t(10;11)(q22;q23) � t(11;11)(q13;q23) � t(11;12)(q23;q13) � t(11;14)(q23;q24) the gene in 14q24 is h-gephyrin � t(11;15)(q23;q14) the gene in 15q14 is AF15q14 � t(11;15)(q23;q15) � t(11;16)(q23;p13) : treatment related ANLL/MDS; most cases are children cases; the gene involved in 16p13 is CBP, a transcriptional adaptor/coactivator � t(11;17)(q23;p13); the gene in 17p13 is GAS7 � t(11;17)(q23;q12); the gene in 17q12 is RARa � t(11;17)(q23;q21) : ANLL; the gene involved in 17q21 is AF17; not to be confused with the in M3 ANLL variant, with involvement of PLZF in 11q23 and RARa in 17q21 � t(11;17)(q23;q25): ANLL and MDS; the gene in 17q25 is MSF/AF17q25 � t(11;18)(q23;q23) � t(11;19)(q23;p13) : ANLL ; the gene in 19p13 is EEN � t(11;21)(q23;q11) � t(11;22)(q23;q13) : ANLL; the gene in 22q13 is P300 � t(11;22)(q23;q11.2) : ANLL; the gene in 22q11.2 is hCDCRel � III- Finally, various other breakpoints with 11q23 have been described, but without gene ascertainment: Xq24, 1q32, 2q37, 7q22, 7q32, 8q11, 9p11, 9q33, 12p13, 12q24, 14q11, 14q32, 17q11, 18q12, 20q13, ...

Additional anomalies

+X and i(7q) in the t(4;11); +8, +19, +21 in the t(6;11); +8 and +19 in the t(9;11); inv(11) in the t(10;11); +X, +6 and +8 in the 19p13.3; +8 in the 19p13.1

Genes involved and ProteinsGene Name MLL

Location 11q23

Dna / Rna 21 exons, spanning over 100 kb; 13-15 kb mRNA; coding sequence: 11.9 kb.

Protein 431 kDa; contains two DNA binding motifs (a AT hook, and Zinc fingers), a DNA methyl transferase motif, a bromodomain; transcriptional regulatory factor; nuclear localisation; wide expression; homology with trithorax (drosophila).

Gene Name variable gene, from a variable chromosome partner (see above)


Dna / Rna these genes appear to have, in most cases, no apparent homology to each other; for DNA and protein description of each, refer to their gene entry.

Result of the chromosomal anomalyHybrid gene

MLL and partners - Editor, 06/2000, last update 09/2001. We implore researchers not to

discover further MLL partners: there is no more room. Description

5' MLL- 3' partner; highly variable breakpoints on the partner Fusion Protein Description

N-term AT hook and DNA methyltransferase from MLL fused to (little or most of) the partner C-term part; the reciprocal ( partner-MLL) may or may not be expressed.

To be noted cases with MLL involvement in rare translocations are yet poorly known;

additional cases are needed to delineate the entities; we propose that detailed cases reports are herein collected and published; if you have a


case with iconography, please, contact us

BibliographyAcute leukemia with chromosome translocation (4;11): 7 new patients and analysis of 71 cases.Lampert F, Harbott J, Ludwig WD, Bartram CR, Ritter J, Gerein V, Neidhardt M, Mertens R, Graf N, Riehm H Blut. 1987 Jun;54(6):325-35. Medline 3496135

Leukemia. 1989 Oct;3(10):695-8. Review.

Characteristics of trisomy 11 in childhood acute leukemia with review of the literature.Ingram L, Raimondi SC, Mirro J Jr, Rivera GK, Ragsdale ST, Behm F

Medline 2674563

Implication of prior treatment with drug combinations including inhibitors of topoisomerase II in therapy-related monocytic leukemia with a 9;11 translocation.

Medline 2177642

Albain KS, Le Beau MM, Ullirsch R, Schumacher H Genes Chromosomes Cancer. 1990 May;2(1):53-8. Review.

Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): a collaborative study of 40 casesPui CH, Frankel LS, Carroll AJ, Raimondi SC, Shuster JJ, Head DR, Crist WM, Land VJ, Pullen DJ, Steuber CP, et al Blood. 1991 Feb 1;77(3):440-7. Medline 1991161 Cytogenetic heterogeneity in t(11;19) acute leukemia: clinical, hematological and cytogenetic analyses of 48 patients--updated published cases and 16 new observations.Huret JL, Brizard A, Slater R, Charrin C, Bertheas MF, Guilhot F, Hahlen K, Kroes W, van Leeuwen E, Schoot EV, et al Leukemia. 1993 Feb;7(2):152-60. Review. Medline 8426468 Childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): an update.Pui CH, Carroll LAJ, Raimondi SC, Shuster JJ, Crist WM, Pullen DJ Blood. 1994 Apr 15;83(8):2384-5. No abstract available. Medline 8161808

Bernard OA, Berger R

Molecular basis of 11q23 rearrangements in hematopoietic malignant proliferations.


Genes Chromosomes Cancer. 1995 Jun;13(2):75-85. Review. Medline 7542910 Self-fusion of the ALL1 gene. A new genetic mechanism for acute leukemia.Schichman SA, Canaani E, Croce CM JAMA. 1995 Feb 15;273(7):571-6. Review Medline 7837391

11q23 rearrangements in acute leukemia.

Rubnitz JE, Behm FG, Downing JR Leukemia. 1996 Jan;10(1):74-82. Review. Medline 8558942 Chromosome abnormalities in leukaemia: the 11q23 paradigm.Young BD, Saha V Cancer Surv. 1996;28:225-45. Review. Medline 8977038 Adenoviral E1A-Associated Protein p300 Is Involved in Acute Myeloid Leukemia With t(11; 22)(q23; q13).Ida K, Kitabayashi I, Taki T, Taniwaki M, Noro K, Yamamoto M , Ohki M, Hayashi Y. Blood 1997; 90: 4699-4704. Medline 98052522

Medline 9226152

All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders.Rowley JD, Reshmi S, Sobulo O, Musvee T, Anastasi J, Raimondi S, Schneider NR, Barredo JC, Cantu ES, Schlegelberger B, Behm F,Doggett NA, Borrow J, Zeleznik-Le N Blood. 1997 Jul 15;90(2):535-41.

Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily.Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC Genomics. 1998 Jan 15;47(2):187-99. Medline 9479491 Ten novel 11q23 chromosomal partner sites. European 11q23 Workshop participants.Harrison CJ, Cuneo A, Clark R, Johansson B, Lafage-Pochitaloff M, Mugneret F, Moorman AV, Secker-Walker LM Leukemia. 1998 May;12(5):811-22. Medline 9593286 Hematologic malignancies with t(4;11)(q21;q23)--a cytogenetic,morphologic,


immunophenotypic and clinical study of 183 cases.European 11q23 Workshop participants.Johansson B, Moorman AV, Haas OA, Watmore AE, Cheung KL, Swanton S, Secker-Walker LM Leukemia. 1998 May;12(5):779-87. Medline 9593281 The t(6;11)(q27;q23) translocation in acute leukemia: a laboratory and clinical study of 30 cases. EU Concerted Action 11q23 Workshop participants.Martineau M, Berger R, Lillington DM, Moorman AV, Secker-Walker LM Leukemia. 1998 May;12(5):788-91. Medline 9593282 Derivative chromosomes of 11q23-translocations in hematologic malignancies. European 11q23 Workshop participants.Johansson B, Moorman AV, Secker-Walker LM Leukemia. 1998 May;12(5):828-33. Medline 9593288 The t(10;11)(p12;q23) translocation in acute leukaemia: a cytogenetic and clinical study of 20 patients. European 11q23 Workshop participantsLillington DM, Young BD, Berger R, Martineau M, Moorman AV, Secker-Walker LM Leukemia. 1998 May;12(5):801-4. Medline 9593284

Martineau M, Berger R, Lillington DM, Moorman AV, Secker-Walker LM

The t(6;11)(q27;q23) translocation in acute leukemia: a laboratory and clinical study of 30 cases. EU Concerted Action 11q23 Workshop participants.

Leukemia. 1998 May;12(5):788-91. Medline 9593282

Proc Natl Acad Sci 1998; 95: 6413-6418.

t(11;22)(q23;q11.2) in acute myeloid leukemia of infant twins fuses MLL with hCDCrel, a cell division cycle gene in the genomic region of deletion in DiGeorge and velocardiofacial syndromes.Megonigal MD, Rappaport EF, Jones DH, Williams TM, Lovett BD, Kelly KM, Lerou PH, Moulton T, Budarf ML, Felix CA.

The translocations, t(11;19)(q23;p13.1) and t(11;19)(q23;p13.3): a cytogenetic and clinical profile of 53 patients. European 11q23 Workshop participants.Moorman AV, Hagemeijer A, Charrin C, Rieder H, Secker-Walker LM Leukemia. 1998 May;12(5):805-10. Medline 9593285 General Report on the European Union Concerted Action Workshop on 11q23, London, UK, May 1997.


Secker-Walker LM Leukemia. 1998 May;12(5):776-8. Medline 9593280 Secondary acute leukemia and myelodysplastic syndrome with 11q23 abnormalities. EU Concerted Action 11q23 Workshop.Secker-Walker LM, Moorman AV, Bain BJ, Mehta AB Leukemia. 1998 May;12(5):840-4. Medline 9593290 Hematological malignancies with t(9;11)(p21-22;q23)--a laboratory and clinical study of 125 cases. European 11q23 Workshop participants.Swansbury GJ, Slater R, Bain BJ, Moorman AV, Secker-Walker LM Leukemia. 1998 May;12(5):792-800. Medline 9593283 ABI-1, a human homolog to mouse Abl-Interactor 1, fuses the MLL gene in acute myeloid leukemia with t(10;11)(p11.2;q23).Taki T, Shibuya N, Taniwaki M, Hanada R, Morishita K, Bessho F, Yanagisawa M, Hayashi Y. Blood 1998; 92: 1125-1130. MLL is involved in a t(2;11)(p21;q23) in a patientwith acute myeloblastic leukemia.Fleischman EW, Reshmi S, Frenkel MA, Konovalova VI, Guleva GP, Kulagina OE, Konstantinova LN, Tupitsyn NN, Rowley JD. Gene Chromosom Cancer 1999; 24: 151- 155. Medline 99101073

Blood 1999; 94 Suppl 1: Abst 3978

t(3;11)(q25;q23) fuses MLL with the GMPS (guanosine 5'-monophosphate synthetase) gene in treatment-related acute myeloid leukemia (AML).Pegram LD, Megonigal MD, Lange BJ, Nowell PC, Rappaport EF, Felix CA. Blood 1999; 94 Suppl 1: Abst 2227 Involvement of the MLL and RARA genes in a patient with acute monocytic leukemia with t(11;17)(q23;q12).Robert L. Redner, Susanne M. Gollin, Sandra S. Kaplan, Sofia Shekhter-Levin.

AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q13q23).Taki T, Kano H, Taniwaki M, Sako M, Yanagisawa M, Hayashi Y. Proc Natl Acad Sci USA 1999; 96: 14535-14540.

The human GRAF gene is fused to MLL in a unique t(5;11)(q31;q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute


myeloid leukemia with a deletion 5q.Borkhardt A, Bojesen S, Haas OA, Fuchs U, Bartelheimer D, Loncarevic IF, Bohle RM, Harbott J, Repp R, Jaeger U, Viehmann S, Henn T, Korth P, Scharr D, Lampert F. Proc Natl Acad Sci U S A. 2000; 97: 9168-9173. Medline 20381355

Oncogene 2000;19: 4446-4450. Medline 20438193

AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid leukaemia with a t(11;15)(q23;q14).Hayette S, Tigaud I, Vanier A, Martel S, Corbo L, Charrin C, Beillard E, Deleage G, Magaud JP, Rimokh R.

Blood 2000; 96 Suppl 1: Abst 2976.

von Bergh A, Beverloo B, Slater R, Groot A, Rombout P, Kluin P, Schuuring E.

A human homologue of the rat gephyrin gene is fused to MLL in a de novo leukemia with t(11;14)(q23;q24).Kuwada N, Kimura F, Matsumura T, Yamashita T, Nakamura Y, Ikeda T, Sato K, Motoyoshi K. Blood 2000; 96 Suppl 1: Abst 4396. Identification of septin 2 as a new partner gene of MLL in infant aml with a complex translocation.Slater DJ, Hilgenfeld E, Rappaport EF, Shah NR, Megonigal MD, Ried T, Felix CA.

Cloning of unknown MLL fusion transcripts identifies two novel MLL fusion partners.

Blood 2000; 96 Suppl 1: Abst 2984. Contributor(s)

08-1998

01-2001

Written Jean-Loup Huret



Updated Jean-Loup Huret


CitationThis paper should be referenced as such : Huret JL . 11q23 rearrangements in leukaemia. Atlas Genet Cytogenet Oncol


Haematol. August 1998 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/11q23ID1030.html Huret JL . 11q23 rearrangements in leukaemia. Atlas Genet Cytogenet Oncol Haematol. September 1998 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/11q23ID1030.html Huret JL . 11q23 rearrangements in leukaemia. Atlas Genet Cytogenet Oncol Haematol. June 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/11q23ID1030.html Huret JL . 11q23 rearrangements in leukaemia. Atlas Genet Cytogenet Oncol Haematol. January 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/11q23ID1030.html Huret JL . 11q23 rearrangements in leukaemia. Atlas Genet Cytogenet Oncol Haematol. August 2003 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/11q23ID1030.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



del(11q) in non-Hodgkin's lymphoma (NHL)

Identity

del(11q) G- banding (the 3 left partial karyotypes) - Courtesy Diane H. Norback, Eric B.

Johnson, Sara Morrison-Delap Cytogenetics at the Waisman Center; R-banding (right) - Editor

Clinics and PathologyDisease the overall incidence in NHL is 4-5%, the highest incidence having been

reported in mantle cell lymphoma, where up to 70% of the cases studied by FISH may harbour a cryptic deletion in association with the classical t(11;14) translocation; FISH detects an approximate 10% incidence of 11q deletion among other histologic subsets of B-NHL; among diffuse large B-cell lymphoma the 11q- chromosome shows a preferential association with the immunoblastic variant; sensitive molecular cytogenetic methods may show 50-70% of T-cell prolymphocytic leukemia to carry an 11q deletion involving the ATM gene

Prognosis a possible association between 11q-/ATM- and poor prognosis in B-cell NHL was reported


the chromosome 11q deletion occurring in NHL most frequently affects the q22-23 bands; the 11q- anomaly occurs as a secondary change in the majority of cases


because the size of the deleted segment may be beyond the resolution power of conventional banding analysis, many cases can only be detected by interphase FISH or other genetic methods using probes targeting the 11q22.3-q23.1 region

Genes involved and ProteinsNote the region of minimal deletion was narrowed down to a 2-3 Mb pair

segment where the ataxia teleangiectasia ( ATM) gene is located;


sequencing studies showed mutation in the remaining ATM allele in a significant fraction of cases

External linksOther database



BibliographyCorrelation of chromosome abnormalities with histologic and immunologic characteristics in non-Hodgkin's lymphoma and adult T-cell leukemia-lymphoma.Fifth International Workshop on chromosomes in leukemia-lymphoma. Blood 1987; 70: 1554-1564. Chromosome 11q rearrangements in B non Hodgkin's lymphoma.Vandenberghe E, De Wolf Peeters C, Wlodarska I et al. Br J Haematol 1992; 81: 212-219. Molecular cytogeneytic delineation of a novel critical genomic region in chromosome bands 11q22.3-23.1 in lymphoproliferative disorders.Stilgenbauer S, Liebish P, James MR, et al. Proc Natl Acad Sci USA 1996; 93: 11837-11841. Cytogenetic and interphase cytogenetic characterization of atypical chronic lymphocytic leukemia carrying BCL1 translocation.Cuneo A, Bigoni R, Negrini M, et al. Cancer Res 1997; 57: 1144-1150. Biallelic mutations in the ATM gene in T-prolymphocytic leukemia.Stilgenbauer S, Schaffner C, Litterst A, et al. Nature Med 1997; 3: 1155-1159. Inactivation of the ATM gene in T-cell prolymphocytic leukemias.Stoppa-Lyonnet D, Soulier J, Laugé A, Dastot H, Garand R, Sigaux F, Stern MH. Blood 1998; 91: 3920-3926. Clinicopthogenetic significance of chromosomal abnormalities in patients with blastic peripheral B-cell lymphoma.Schlegelberger B, Zwingers T, Harder T, Nowotny H, Siebert R, Vesely M, Bartels H, Sonnen R, Hopfinger G, Nader A, Ott G, Muller-Hermelink K, Feller A, Heinz R, for the Kiel-Wien-Lymphoma Study Group. Blood 1999; 94: 3114-3120. Molecular characterization of 11q deletions points to a pathogenetic role of the ATM gene in mantle cell lymphoma.Stilgenbauer S, Winkler D, Ott G et al.


Blood 1999; 94: 3262-3264. Acquired deletion of the ataxia teleangiectasia (ATM) LOCUS in non-Hodgkin's lymphoma: correlation with clinicobiological features.Cuneo A, Bigoni R, Rigolin GM, Roberti MG, Bardi A, Negrini M, Sabbioni S, Russo G, Narducci MG, Minotto C, Agostini P, Campioni D, Milani R, Castoldi GL. J Clin Oncol 2000; 18: 2607-2614. Contributor(s)


CitationThis paper should be referenced as such : Cuneo A and Castoldi G . del(11q) in non-Hodgkin's lymphoma (NHL). Atlas Genet Cytogenet Oncol Haematol. January 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/del11qNHLID2020.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology




Clinics and PathologyDisease the frequency of 7q deletions in unseletced NHL is less than 5%; an

association with splenic marginal zone B-cell lymphomas (MZBCL) was established, with a 20-30% incidence; sensitive molecular genetic studies found a 40% incidence in splenic MZBCL, as against a 7% incidence in other forms of NHL

Prognosis there may be an association of 7q- with tumor progression or transformation into a high-grade MZBCL


7q deletions or unbalanced 7q translocations in NHL usually involve a relatively large segment, usually centered around the 7q22-q32 region


conventional G- or R-banded preparations detect the majority of cases; however some patients with submicroscopic deletion were detected by FISH or loss-of-heterozigosity studies

Genes involved and ProteinsNote the involved gene(s) are unknown; the minimal region of deletion in

MZBCL carrying a 7q- chromosome was narrowed down to a 5cM segment defined by the D7S685 and D7S514 markers; homozygous deletion of the D7S685 was reported, suggesting that a tumor suppressor gene relevant to lymphomagenesis may be located in this region; a recurrent 7q21 translocation involving a small 3.6 Kb segment upstream of the cyclin-dependent kinase 6 gene ( CDK6), with resultant CDK6 overexpression, was described




BibliographyCytogenetic studies in splenic lymphoma with villous lymphocytes.Oscier DG, Matutes E, Gardiner A. Gilde S, Mould S, Brito-Babapulle V, Ellis J, Catovsky D. Br J Haematol 1993; 85: 487-491.


Dysregulation of cyclin dependent kinase 6 expression in splenic marginal zone lymphoma through chromosome 7q translocations.Corcoran MM, Mould SJ, Orchard JA, Ibbotson RE, Chapman RM; Boright AP, Platt C, Tsui LC, Scherer SW, Oscier DG. Oncogene 1999; 18: 6271-6277. 7q31-32 allelic loss is a frequent finding in splenic marginal zone lymphom.Mateo M, Mollejo M, Villuendas R, Algara P, Sanchez-Beato M, Martìnez P, Piris MA.Am J Pathol 1999; 154: 1583-1589. Molecular cytogenetic characterization of marginal zone B-cell lymphoma: correlation with clinicopathologic findings in 14 cases.Cuneo A, Bigoni R, Roberti MG, Milani R, Agostini P, Cavazzini F, Minotto C, De Angeli C, Bardi A, Tammiso E, Negrini M, Cavazzini P, Castoldi G. Haematologica 2001 in press Contributor(s)

01-2001

Written Antonio Cuneo, Gianluigi Castoldi

CitationThis paper should be referenced as such : Cuneo A and Castoldi G . del(7q) in non-Hodgkin's lymphoma (NHL). Atlas Genet Cytogenet Oncol Haematol. January 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/del7qNHLID2082.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



t(1;14)(p22;q32) in non Hodgkin's lymphoma (NHL)

Clinics and PathologyDisease the translocation is cytogenetically detectable in a minority of extranodal

MALT lymphomas; irrespective of the presence of the 1;14 translocation, mutation or deletion of the BCL10 gene located at 1p22 can be detected by molecular genetic methods in 5-10% of extra-nodal MALT lymphomas, follicle centre cell lymphoma and diffuse large B-cell lymphoma; among MALT lymphoma a preferential association was noted with high-grade histology

Prognosis in MALT lymphoma there may be an association with aggressive histology and antibiotic-unresponsive forms

CytogeneticsCytogenetics Morphological the translocation is readily detectable by conventional karyotyping

Genes involved and ProteinsNote the breakpoints on chromosome 1p22 are located upstream of the

promoter of the BCL10 gene, which shows inactivating mutations or deletions

Gene Name BCL10

Location 1p22 Protein 322 amino acids; contains a caspase recruitment domain; role in the

apoptosis Gene Name IgH

Location 14q32


t(1;14)(p22;q32) in non Hodgkin's lymphoma (NHL)


t(1;14)(p22;q32) in non Hodgkin's Other

database CancerChromosomes (NCBI) lymphoma (NHL)

BibliographyCytogenetic study of B-cell lymphoma of muca-associated lymphoid tissue.


Wotherspoon AC, Pan L, Diss TC, Isacsson PG. Cancer Genet Cytogenet 1991; 58: 35-38.

Cell 1999; 96: 35-45.

Zhang Q, Siebert R, Yan M, Hinzmann B, Cui X, Xue L, Rakestraw KM, Naeve CW, Beckmann G, Weisenburger DD, Sanger WG, Nowotny H, Vesely M, Callet-Bauchu E, Salles G, Dixit VM, Rosenthal A, Schlegelberger B, Morris SW.

BCL10 gene mutation in lymphoma.

BCL10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types.Willis TG, Jadayel DM, Du MQ, Peng H, Perry AR, Abdul-Rauf M, Price H, Karran L, Majekodumni O, Wlodarska I, Pan L, Crook T, Hamoudi R, Isaacson PG, Dyer MJS.

Inactivating mutations and overexpression of BCL10, a caspase recruitment domain containing gene, in MALT lymphoma with t(14)(p22;q32).

Nat Genet 1999; 22: 63-68.

Du MQ, Peng W, Liu H, Hamoudi RA, Diss TC, Willis TJ, Ye H, Dogan H, Wotherspoon AC, Dyer MJS, Isacsoon PG. Blood 2000; 95: 3885-3890.


Written Antonio Cuneo, Gianluigi Castoldi

CitationThis paper should be referenced as such : Cuneo A and Castoldi G . t(1;14)(p22;q32) in non Hodgkin's lymphoma (NHL). Atlas Genet Cytogenet Oncol Haematol. January 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t114ID2044.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



t(5;10)(q33;q21)

Clinics and PathologyDisease myeloid lineage Phenotype / cell stem origin

atypical chronic myeloid leukemia (CML), Philadelphia negative, bcr-abl negative with eosinophilia

massive splenomegaly in one case; some clinical features of accelerated CML

extramedullary hemopoiesis in the spleen

Epidemiology only two cases available Clinics

Cytology peripheral blood leukoerythroblastosis; bone marrow granulocytic hyperplasia, bone marrow fibrosis (grade III-IV reticulin), dry tap

Pathology Treatment control of disease by hydroxyurea in both cases

CytogeneticsCytogenetics Morphological cytogenetic result: add(5q), del(10q)

Probes cosB for PDGFBR (5q33); PAC29F6 for H4/D10S170 (10q21)

Genes involved and ProteinsGene Name PDGFRB (Platelet Derived Growth Factor Receptor Beta)

Location

Gene Name

5q33 Protein transmembrane and tyrosine kinase domains

H4(D10S170)

Protein Location 10q21

carboxyterminal putative SH3 binding site; cytoskeletal protein?

Result of the chromosomal anomalyHybrid gene Transcript

H4-PDGFBR chimeric RNA constantly present


External linksOther database t(5;10)(q33;q21) Mitelman database (CGAP - NCBI)

Other database t(5;10)(q33;q21) CancerChromosomes (NCBI)



BibliographyAnastasiadou E et al.

Siena S et al.

Kulkarni S et al.

Blood 1999; 94 (Suppl.1): 51a.

Haematologica 1999; 84: 369.

Cancer Res 2000; 60: 3592. Contributor(s)

01-2001

Written Cristina Mecucci

CitationThis paper should be referenced as such : Mecucci C . t(5;10)(q33;q21). Atlas Genet Cytogenet Oncol Haematol. January 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/t510ID1166.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



+3 or trisomy 3 in non Hodgkin's lymphoma (NHL)

Clinics and PathologyDisease trisomy 3 occurs more frequently in T-cell lymphomas than in B-cell

lymphomas � globally, 20-30% of T-NHL may carry trisomy 3, the highest incidence having been noted in lymphoepithelioid lymphoma, in low-grade peripheral T-cell lymphoma, in angioimmonoblastic lymphadenopathy and in adult T-cell leukemia-lymphoma � trisomy 3 is relatively rare in B-NHL, with the exception of marginal zone lymphomas (MZL) and mantle cell lymphoma (MCL); in MZL, total or partial trisomy 3 may occur in 50-70% of cytogenetically abnormal cases, with a reported incidence by interphase FISH in the 50-85% range; the incidence does not appear to vary according to the clinicopathologic features, with similar frequency in the extra-nodal MALT lymphoma, in the nodal and the splenic form of MZL; trisomy 3/3q was reported in 10-15% of MCL with an higher incidence (up to 40%) by molecular cytogenetic techniques; sporadically, other low-grade and high grade B-lymphoid tumors may carry trisomy 3/3q

Prognosis the prognostic significance of trisomy 3 in T-cell and B-cell lymphomas is unknown; there does not appear to be a role for trisomy 3 in tumor progression from low-grade MALT lymphoma to the high grade form, whereas gains of 3q may be associated with the aggressive blastoid variant of MCL


trisomy 3 may be total or partial; commonly overrepresented segments in partial trisomy 3 include the q21-23 region and the q25-29 region; total/partial trisomy 3 may occur as an isolated anomaly in a minority of cases


the anomaly is readily detectable by G- and R-banding in most cases; however, FISH using a centromeric probe is more sensitive than conventional cytogenetics, allowing for the study of non-dividing cells and for the detection of partial trisomy in complex karyotypes with marker chromosomes

Genes involved and ProteinsNote the gene(s) involved in the transformation process by gene dosage

effect or by other mechanisms are not known



+3 or trisomy 3 in non Hodgkin's lymphoma (NHL)


BibliographyCorrelation of chromosome abnormalities with histologic and immunologic characteristics in non-Hodgkin's lymphoma and adult T-cell leukemia-lymphoma.

Blood 1994; 83: 505-511.

Dierlamm J, Pittaluga S, Wlodarska I, Stul M, Thomas J, Boogaerts M, Michaux L, Driessen A, Mecucci C, Cassiman JJ, De Wolf-Peeters C, van Den Berghe H. Blood 1996; 87: 299-307.

Michaux L, Dierlamm J, Wlodarska I, Criel A, Louwagie A, Ferrant A, hagemeijer A, Van Den Berghe H.

Beà S, Ribas M, Hernàndez JM, Bosch F, Pinyol M, Hernàndez L, Garcìa JL, Flores T, Gonzàles M, Lòpez-Guillermo A, Piris MA, Cardesa A, Montserrat E, Mirò R, Campo E. Blood 1999; 93: 4365-4374.

Gastric low grade lymphoma, high grade MALT lymphoma and diffuse large B cell lymphoma show different frequencies of trisomy.

Fifth International Workshop on chromosomes in leukemia-lymphoma. Blood 1987; 70: 1554-1564.

Cytogenetic findings in peripheral T-cell lymphomas as a basis for distinguishing low-grade and high-grade lymphomas.Schlegelberger B, Himmler A, Godde E, Grote W, Feller AC, Lennert K.

Marginal zone B-cell lymphomas of different sites share similar cytogenetic and morphologic features.

Trisomy 3q11-q29 is recurrently observed in B-cell non-Hodgkin's lymphomas associated with cold agglutinin syndrome.

Ann Hematol 1998; 76: 201-204. Increased number of chromosomal imbalances and high-level DNA amplifications in mantle cell lymphoma are associated with blastoid variants.

Hoeve MA, Gisbertz IAM, Schouten HC, Schuuring E, Bot FJ, Hermans J, Hopman A, Kluin PhM, Arends J-W, van Krieken JHJM. Leukemia 1999; 13: 799-807.

Secondary chromosome changes in mantle cell lymphoma: Cytogenetic and fluorescence in situ hybridization studies.Bigoni R, Cuneo A, Milani R, Roberti MG, Bardi A, Rigolin GM, Cavazzini F, Agostini P, Castoldi G.


Leuk Lymphoma 2001, in press. Contributor(s)


CitationThis paper should be referenced as such : Cuneo A and Castoldi G . +3 or trisomy 3 in non Hodgkin's lymphoma (NHL). Atlas Genet Cytogenet Oncol Haematol. January 2001 . URL : http://www.infobiogen.fr/services/chromcancer/Anomalies/tri3NHLID2008.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



-Y

Y loss in leukemia

IdentityLoss of the Y chromosome from individual metaphases is common in metaphase cells from both PHA-stimulated lymphocytes and spontaneously dividing bone marrow cells. The frequency of Y loss is greater in older men, and the size of the 45,X,-Y cell population probably increases gradually with advancing age. (In females, a corollary loss of one X chromosome also occurs with advancing age.) This natural phenomenon challenges our ability to distinguish between a normal and a disease-associated 45,X,-Y clone.

Note

Clinics and PathologyDisease -Y is frenquently observed in myeloproliferative diseases (MPD),

myelodysplasic syndromes (MDS), acute non lymphocytic leukemias (ANLL), and can also be seen in lymphoproliferations

Epidemiology In CML with t(9;22) and in ANLL with a t(8;21), loss of the Y chromosome tends to occurs at a younger age than in the general population

Clinics � Partial or complete reappearance of the Y chromosome has been described in several cases of ANLL in remission. In most or all of these ANLL cases, the 45,X,-Y cell population represented 80-100% of pre-remission metaphases. These observations support the interpretation that the leukemia cell karyotype is 45,X,-Y. � In MDS, the proportion of -Y cells has been observed to increase, decrease, remain stable, or fluctuate up and down on follow-up studies. � In four cases of Hodgkin disease, simultaneous fluorescence immunophenotyping and FISH showed that the -Y cell population was probably independent of the Hodgkin disease in at least two of the patients. It is notable that the -Y cells represented fewer than 10-15% of the metaphase cells in all four cases.

Cytology no known association Prognosis In ANLL, a 45,X,-Y karyotype is believed to have an intermediate

prognosis. In MDS, the prognosis appears to be neutral or favorable. There are insufficient data for MPD or lymphoproliferative disease

Cytogenetics


Cytogenetics Morphological

� In PHA-stimulated lymphocyte karyotype studies of males, about 2% have one or more cells with loss of the Y chromosome. Cells with -Y are observed more often in males over age 55 than in younger males. In all age groups, the proportion of -Y cells is usually under 10%. � The pattern of Y loss is more striking in bone marrow aspirate karyotype studies. Here, clonal Y chromosome loss as a sole abnormality in the karyotype is a common finding. A 45,X,-Y karyotype is observed in about 6% of bone marrow karyotype studies from males, and it represents 15-20% of abnormal karyotypes. � The frequency of -Y cells increases with advancing age and is significantly greater in cases with MDS, MPD, ANLL, or lymphoproliferative disease than in subjects who have no evidence of disease. Subjects with no evidence of disease rarely exhibit more than 75% of cells with 45,X,-Y. Thus, if fewer than 75% of metaphase cells are -Y, the disease association is uncertain. However, if 75-100% of metaphase cells are -Y, the karyotype probably is disease-associated, even in older men. � Chromosome rearrangements involving the Y chromosome are rare in cancer and leukemia. Loss of the Y chromosome, in contrast, is a common secondary change in cancer cells and in a few leukemias (see below).

Probes all available probe for the Y chromosome Additional anomalies

In association with t(9;22) in CML and with t(8;21) in FAB-M2 ANLL, loss of the Y chromosome is generally considered a secondary event of no added clinical significance.

Genes involved and ProteinsNote genes involved, if any, are unknown

External linksOther database -Y Mitelman database (CGAP - NCBI)

To be noted It is not known whether the Y chromosome loss is the critical mutational

event. Likewise, it is not known whether the Y chromosome loss is a secondary genetic change, or if the critical (submicroscopic) genetic change simply occurs by chance in a -Y cell. Speculatively, loss of the Y could provide a proliferative advantage simply because it tends to replicate late in S-phase. Its loss might therefore shorten the cell cycle slightly.

BibliographyAge-associated aneuploidy: loss of Y chromosome from human bone marrow cells with aging.Pierre RV, Hoalgland HC.


Cancer 1972; 30: 889-894. Medline 4116908 Y chromosome loss in leukemias.Berger R, Bernheim A. Cancer Genet Cytogenet 1979; 1: 1-8. Chromosomes and causation of human cancer and leukemia XXXV. The missing Y in acute non-lymphocytic leukemia (ANLL).Abe S, Golomb HM, Rowley JD, Mitelman F, Sandberg AA. Cancer 1980; 45: 84-90. Medline 6985828 Loss of the Y chromosome in acute myelogenous leukemia: a report of 13 patients.Holmes RI, Keating MJ, Cork A, Trujillo JM, McCredie KB, Freireich EJ. Cancer Genet Cytogenet 1985;17:269-278. Medline 3859363 Acute myelogenous with a 8;21 translocation. A report on 148 cases from the Groupe Fran&ccdil;ais de Cytogégétique Hématologique.Groupe Fran&ccdil;ais de Cytogénétique Hématologique. Cancer Genet Cytogenet 1990; 44: 169-179. The frequency of aneuploidy in cultured lymphocytes is correlated with age and gender but not reproductive history.Nowinski GP, Van Dyke DL, Tilley B, Babu VR, Worsham MJ, Wilson GN, Weiss L. Am J Hum Genet 1990; 46:1101-1111. Medline 2339703 Loss of the chromosome from normal and neoplastic bone marrows.United Kingdom Cancer Cytogenetics Group (UKCCG). Genes Chromosom Cancer 1992; 5: 83-88. X and Y chromosome loss as sole abnormality in acute non- lymphocytic leukemia (ANLL).Riske CB, Morgan R, Ondreyco S, Sandberg AA. Cancer Genet Cytogenet 1994; 72: 44-47. Medline 8111738 Y chromosome loss in chronic myeloid leukemia detected in both normal and malignant cells by interphase fluorescence in situ hybridization.Kirk JA, Van Devanter DR, Biderman J, Bryant EM. Genes Chromosom Cancer 1994; 5: 83-88. Loss of Y Chromosome. An age-related event or a cytogenetic marker of a


malignant clone?Abelovich D, Yehuda O, Ben-Neriah S, Or R. Cancer Genet Cytogenet 1994:76:70-71. Clarification of dubious karyotypes in Hodgkin's disease by simultaneous fluorescence immunophenotyping and interphase cytogenetics (FICTION).Weber-Matthiesen K, Deerberg J, Poetsch M, Grote W, Schlegeiberger B. Cytogenet Cell Genet 1995;70:243-245. Medline 7789181 Clinical significance of Y chromosome loss in hematologic disease.Wiktor A, Rybicki BA, Piao ZS, Shurafa M, Barthel B, Maeda K, Van Dyke DL. Genes Chromosomes Cancer 2000;27:11-14. Medline 10564581 Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study.Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, theil KS, Mohamed A, Paietta E, Willman CL, Head DR, Rowe JM, Forman SJ, Appelbaum FR. Blood 2000;96:4075-4083. Medline 11110676 Contributor(s)Written 01-

1999 Fran&ccdeil;ois Desangles

01-2001

Updated Daniel L. Van Dyke

CitationThis paper should be referenced as such : Desangles F . -Y,Y loss in leukemia. Atlas Genet Cytogenet Oncol Haematol. January 1999 . URL : http://AtlasGeneticsOncology.org/Anomalies/YlossID1089.html Van Dyke DL . -Y,Y loss in leukemia. Atlas Genet Cytogenet Oncol Haematol. January 2001 . URL : http://AtlasGeneticsOncology.org/Anomalies/YlossID1089.html




Nervous system: Astrocytic tumors

ClassificationNote Astrocytic tumors comprise a wide range of neoplasms that differ in their

location within the central nervous system (CNS), age and gender distribution, growth potential, extent of invasiveness, morphological features, tendency for progression and clinical course; there is increasing evidence that these differences reflect the type and sequence of genetic alterations acquired during the process of transformation.

The following clinicopathological entities can be distinguished :

� Fibrillary Astrocytomas (Grade II) � Pilocytic Astrocytomas (Grade I)

� Anaplastic Astrocytomas (Grade III) � Glioblastoma Multiforme (Grade IV)

Clinics and PathologyEtiology � gliomas have been observed following therapeutic irradiation.

� familial clustering of gliomas is not uncommon: the association with defined inherited tumor syndrome incuding the Li-Fraumeni syndrome, Turcot syndrome, and the NF1 syndrome

3. Anaplastic Astrocytomas / Grade III: anaplastic astrocytomas occur in the same locations as astroc

Epidemiology diffuse astrocytomas are the most frequent intracranial neoplasm and account for more than 60% of all primary brain tumors; the incidence differs between regions, but there are 5 to 7 new cases per 100.000 population per year

Clinics 1. Pilocytic Astrocytomas / Grade I: pilocytic astrocytomas arise throughout the neuraxis and are common in children and in young adults; pilocytic tumors of the optic nerve cause loss of vision; pilocytic astrocytoma of the hypothalamus and third ventricular region primarily affect children; but tumors of the cerebral hemispheres generally occur in patients older than those with visual system or hypothalamic involvment

2. Fibrillary Astrocytomas / Grade II: fibrillary astrocytomas arise in the cerebral hemisphere of young to middle-aged adults and the brain stem of children; occasional examples occur in the cerebellum or spinal cord; at any site these astrocytomas must be distinguished from pilocytic astrocytomas; all such tumors are pilocytic astrocytomas in the optic nerve whereas most are of the fibrillary type in the brain stem

ytomas (I-II) and


glioblastoma, but the majority affect the cerebral hemispheres; anaplastic astrocytomas generally occur in patients a decade older than those with better differenciated astrocytomas and a decade younger than those with glioblastomas

another subgroup of glioblastoma can be distinguished: the giant cell glioblastomas; histologically it is a glioblastoma with giant cells (500 mm in diameter): it develops clinically "de novo "; it is associated with a favorable prognosis

4. Glioblastoma Multiforme / Grade IV: glioblastoma is by far the most common glioma; it affects principally the cerebral hemispheries in adults and the brain stem in children; but they are most frequent after the fifth decade; most glioblastomas are solitary but occasional examples are geographically separate in the same patient and warrant the designation " multicentric "; usually, it appears as a central area of hypodensity surrounded by a ring of contrast enhanced and penumbra of cerebral oedema glioblastoma multiforme may develop de novo (primary glioblastoma) or though progression from low-grade or anaplastic astrocytoma (secondary glioblastoma); patients with a primary glioblastoma are usually older, present a rapid tumor progression and a poor prognosis; patient with secondary glioblastomas are younger and tumor progress more slowly, with a better prognosis; these two groups are histologically indistinguishable

Pathology 1. Pilocytic Astrocytomas / Grade I: this predominantly peadiatric brain tumor is a circumscribed astrocytoma composed in varying proportions of compacted and loose textured astrocytes associated with rosenthal fibers, eosinophilic granular bodies, or both; the lesion described is sometimes referred to as the " juvenile pilocytic astrocytoma "

2. Fibrillary Astrocytomas / Grade II: this tumor is a well differanciated diffusely infiltrating neoplasm of fibrillary astrocytes

3. Anaplastic Astrocytomas / Grade III: this tumor is an astrocytic tumor of fibrillary type which is intermediate in differenciation between the better differenciated astrocytoma and glioblastoma; it is an astrocytic neoplasm that typically exceeds well differenciated astrocytoma in terms of cellularity, nuclear pleomorphism and hyperchromasia necrosis of glioblastoma

4. Glioblastoma Multiforme / Grade IV: this tumor is a highly malignant glioma most closely related to fibrillary or diffuse astrocytic neoplasms; glioblastomas are cellular masses with varied tissue patterns; it appears either infiltrating or discrete, with typical or atypical mitoses, endothelial vascular proliferation and necrosis


Treatment treatment differs according to grade and location of tumor pilocytic astrocytomas can be cured by complete resection of tumor; if exeresis is not possible due to the location of the tumor, chemotherapy is indicated in young children and radiotherapy in adults in fibrillary astrocytomas, the treatment consists of total and extent resection of tumor in anaplastic tumors and glioblastoma multiforme, the treatment consists of total resection and radiotherapy and chemotherapy after surgery in low grade astrocytomas, a correlation of proliferation was reported (Ki67 index) with clinical outcome; the proliferative potential correlates inversely with survival and time to recurrence; the mean survival time after surgery is 6-8 years in low-grade astrocytomas; after surgery, the prognosis depends on whether the neoplasm undergoes progression to a more malignant phenotype; in pilocytic astrocytomas, total cure is possible after total resection; in fibrillary astrocytomas reccurrence is frequent . in anaplastic astrocytomas and in glioblastomas, evaluation of the extent of resection can be a prognostic factor; prognosis is generally poor (about one year); patients below 45 yrs have a considerably better prognosis than elderly patients; primary glioblastomas have a short clinical history with a poor prognosis; survival is better in secondary glioblastomas

Prognosis


� In astrocytomas grade I, normal karyotype is observed most frequently; among the cases with abnormal karyotypes, the most frequent chromosomal abnormalityis loss of the X and Y sex- chromosomes; loss of 22q is found in 20-30% of astrocytomas; other abnormalities observed in low grade tumors include gains on chromosome 8q, 10p, and 12p, and losses on chromosomes 1p, 4q, 9p, 11p 16p, 18 and 19 � In anaplastic astrocytomas, chromosome gains or losses are frequent: trisomy 7 (the most frequent), loss of chromosome 10, loss of chromosome 22, loss of 9p, 13q; other abnormalities, less frequently described are: gains of chromosomes 1q, 11q, 19, 20, and Xq � Glioblastomas show several chromosomal changes: by frequency order, gain of chromosome 7 (50-80% of glioblastomas), double minute chromosomes, total or partial monosomy for chromosome 10 (70% of tumors) associated with the later step in the progression of glioblastomas partial deletion of 9p is frequent (64% of tumors): 9pter-23; partial loss of 22q in 22q13 is frequently reported loss or deletion of chromosome 13, 13q14-q31 is found in some glioblastomas trisomy 19 was reported in glioblastomas by cytogenetic and comparative genomic hybridization (CGH) analysis; the loss of 19q in 19q13.2-qter was detected by loss of heterozigocity (LOH) studies in glioblastomas deletion of chromosome 4q, complete or partial gains of chromosome


20 has been described; gain or amplification of 12q14-q21 has been reported the loss of chromosome Y might be considered, when it occurs in addition to other clonal abnormalities

Genes involved and ProteinsNote � Alteration of genes involved in cell-cycle control:

it is known that the progression of the-cell cycle is controled by positive and negative regulators; some autors report alteration in cell-cycle gene expression in human brain tumors the p16 gene and the p15 gene are located in 9p21, a chromosome region commonly deleted in astrocytomas; expression of p16 gene is frequently altered in these tumors: in 33-68% of primary glioblastomas and 25% of anaplastic astrocytomas the Rb gene located on13q chromosome plays an important role in the malignant progression of gliomas the p53 gene is a tumor suppressor gene located on chromosome 17p13.1; loss or mutation of p53 gene has been detected in many types of gliomas and represents an early genetic event in these tumors overexpression of MDM2 is also seen in primary glioblastomas others oncogenes have been found to be amplified in a few cases of astrocytomas : oncogenes Gli, MYC, MYCN, MET and N-Ras � Loss or inactivation of tumor suppressor genes: in addition to p53 gene, others tumor suppression genes play a role in astrocytomas loss of chromosome 10 is the most frequent abnormality associated with the progression of malignant astrocytic tumors; more than 70% of glioblastomas show LOH on chromosome 10; amplification of EGFR is always associated with loss of chromosome 10 the PTEN gene located at the 10q23 locus is implicated more frequently in glioblastomas than in anaplastic astrocytomas another suppressor gene the MXII gene has also been located on the distal portion of chromosome 10 at the 10q24 at the 10q24-p25 locus homozygous deletion in the DMTB gene located on the region 10q25.3-26.1 have been reported in glioblastomas the LG11 novel gene located in 10p24 region is a suppressor gene rearranged in several glioblastomas tumors allelic loss of chromosome 22q wich contains the neurofibromatosis type 2, tumor suppressor gene NF2 is observed in 20-30% of astrocytomas. But another possibility is the involvement of another gene located on chromosome 22 in the tumorogenesis of astrocytomas most of these genes participate in the progression of astrocytomas (fig 1) � Expression of growth factors and growth factor receptors: the epidermal growth factor receptor (EGFR) coded by the EGFR cellular oncogene is located on human chromosome 7 at locus 7p12-p14; EGRF is amplified in 40-60% of glioblastomas; it constitues a hallmark: primary glioblastomas rarely contain EGFR overexpression; patients with anaplastic astrocytomas or glioblastomas have a poorer


prognosis when EGFR gene amplification is present; amplification could be a significant prognostic factor in these tumors over expression of PDGFR-a (platelet derived growth factor) is asociated with loss of heterozygosity of chromosome 17p and p53 mutations in secondary glioblastomas others growth factors expressed in gliomas include fibroblast growth factors (FGFs), insulin-like growth factors (IGFs), and vascular endothelial growth factor (VEGF)

Molecular pathways in the progression of astrocytomas (from Ho-Keung and Paula

Y.P. Lam) BibliographyGene amplification in malignant human gliomas : clinical and histopathologic aspects.Bigner SH, Burger PC, Wong AJ, Werner MH, Hamilton SR, Muhlbaier LH, Vogelstein B, Bigner DD. J Neuropathol Exp Neurol 1988; 47: 191-205. Cytogenetics of human brain tumors.Bigner SH, Mark J, Bigner DD. Cancer Genet Cytogenet 1990; 47 : 141-154. Chromosome abnormalities in low-grade central nervous system tumors.Griffin CA, Long PP, Carson BS, Brem H. Cancer Genet Cytogenet 1992; 60: 67-73. Karyotypes in 90 human gliomas.Thiel G, Losanowa T, Kintzel D, Nish G, Martin H, Vorpahl K, Witkowski R. Cancer Genet Cytogenet 1992; 58: 109-120.


Loss of heterozygoty for 10q loci in human gliomas.

Alterations of the TP53 gene in human gliomas.

Gene amplification in human gliomas.

Refined deletion mapping of chromosome 19q glioma tumor suppressor gene to the D19S412-STD interval.

Oncogene 1996; 13: 983-994.

Schlegel J, Scherthan H, Arens N, Stumm G, Kiessling M.

Rasheed BK, Fuller GN, Friedman AH, Bigner DD, Bigner SH. Genes Chromosom Cancer 1992; 5: 75-82.

Molecular analysis of genomic abnormalities in human gliomas.Bello MJ, de Campos JM, Kusak ME, Vaquero J, Sarasa JL, Pestana A, Rey JA. Cancer Genet Cytogenet 1994. 73: 122-129.

Rasheed BKA, McLendon RE, Herndon JE, Friedman HS, Friedman AH, Bigner DD, Bigner SH. Cancer Res 1994; 54: 1324-1330. Amplification of the epidermal growth factor receptor gene correlates with different growth benaviour in human glioblastoma.Schlegel J, Merdes A, Stumm G, Albert FK, Forsting M, Hynes N, Kiessling M. Int J Cancer 1994; 56: 72-77.

Collins VP. Glia 1995; 15: 289-296. MTS1/p16/CDKN2 lesions in primary glioblastomas multiforme.Moulton T, Samara G, Chung WY, Yuan L, Desai R, Sisti M, Bruce J, Tycko B. Am J Pathol 1995; 146: 613-619. EGFR gene amplification-rearrangement in human glioblastomas.Schwechheimer K, Huang S, Cavenee WK. Int J Cancer 1995; 62: 145-148.

Rosenberg JE, Lisle DK, Burwick JA, Ueki F, von Deimling A, Mohrenweiser HW, Louis DN. Oncogene 1996; 13 : 2483-2485.

Characterisation of genomic alterations associated with glioma progression by comparative genomic hybridization.Weber RG, Sabel M, Reifernberger J, Sommer C, Oberstra_ J, Reifernberger G, Kiessling M, Cremer T.

Detection of complex genetic alerations in human glioblastoma multiforme using comparative genomic hybridization.


J Neuropathol Exp Neurol 1996; 55: 81-87. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.

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Steck P, Pershouse M, Jasser S, Yung A, Lin H, Ligon A, Langford L, Baumgard M, Hattier T, Davis T , Frye C, Hu R, Swedlund B, Teng D, Tavtigian S.

MX11, a putative suppressor gene, suppresses growth of human glioblastoma cells.

Cancer Res 1997; 57: 4187-4190.

Chernova OB, Somerville RP, Cowell JK.

The molecular genetics of central nervous system tumors.

Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang S, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner S, Giovanella B, Ittman M, Tycko B, Hibshoosh H, Wigler M, Parsons R. Science 1997; 274: 1943-1947.

Brain tumors. In : Cytogenetic Cancer Markers.Shapiro JR, Scheck AC.

Identification of a candidate tumor suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers.

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Wechsler DS, Shelly CA, Petroff CA, Dang CV. Cancer Res 1997; 57: 4905-4912.

PTEN gene mutations are seen in high-grade but not in low grade gliomas.Rasheed BKA, Stenzel TT, McLendon RE, Parsons R, Friedman AH, Friedman HS, Bigner DD, Bigner SH.

A novel gene, LG11, from 10q24 is rearranged and down regulated in malignant brain tumors.

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Ho-Keug NG, Lam YP. Pathology 1998; 30: 196-202.

Investigation of genetic alterations associated with the grade of astrocytic tumors by comparative genomic hybridization.Nishizaki T, Ozaki S, Harada K, Ito H, Arai H, Beppu T, Sasaki H. Genes Chromosom Cancer 1998; 21: 340-346.

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Semin Surg Oncol 1998; 14 : 3-12. Pilocytc astrocytoma.In Pathology and Genetics of Tumors of the NervousBurger PC, Scheithauer BW, Paulus W, Giannini C, Kleihues P. System-Kleihues P, Cavenee WK (eds) 2000; IARC Press, pp 29-33. Cytogenetic and molecular abnormalities in astrocytic gliomas (Review).Goussia AC, Agnantis NJ, Rao JS, Kiristis AP. Oncol Report 2000; 7: 401-412. REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s)

11-2000

Written Anne Marie Capodano

CitationThis paper should be referenced as such : Capodano AM . Nervous system: Astrocytic tumors. Atlas Genet Cytogenet Oncol Haematol. November 2000 . URL : http://AtlasGeneticsOncology.org/Tumors/AstrocytID5007.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



Beckwith-Wiedemann syndrome IdentityOther names EMG syndrome

Inheritance incidence of 7/105; given the variable expression of the symptoms, the actual frequency is likely to be higher; generally there is sporadic occurrence of the syndrome (85%); inheritance is mostly maternal (imprinting) with a more severe phenotype after maternal transmission

ClinicsNote clinically and genetically heterogeneous; three distinct regions on 11p15

have been associated with BWS (BWSCR1/2/3); BWSCR2 seems to be particularly associated with hemihypertrophy

Phenotype and clinics

multiple features that occur variably; most prominent is the EMG triad (exomphalos-macroglossia-gigantism): apart from the abdominal wall defects and pre- and postnatal growth abnormalities, earlobe pits or creases, facial nevus flammeus, hypoglycemia, renal abnormalities and hemihypertrophy (unilateral overgrowth) are frequently seen

Patient with Beckwith-Wiedemann syndrome. The face shows the enlarged tongue

(macroglossia), the ear the typical earlobe creases - Marcel Mannens


Neoplastic risk

the increased risk for childhood solid tumours is 7.5% (thousand fold increase); tumours most frequently seen are nephroblastoma (Wilms tumour), adrenocortical carcinoma, rhabdomyosarcoma and hepatoblastoma; clinical risk factors are hemihypertrophy and nephromegaly; genetic risk factors are uniparental disomy (UPD) and H19/IGF2 imprinting defects

Treatment in general surgical correction of the abdominal wall defects and macroglossia; monitoring the glycemia during the first 3 days and early treatment of hypoglycemia (deleterious for central nervous system) is of importance to avoid further complications; frequent screening for tumour development

Prognosis clinical features tend to become less with ageing; tumour risk decreases strongly after the 4-7th year of birth

CytogeneticsInborn conditions

paternal duplications of chromosome region 11p15, maternal translocations involving chromosome region 11p15.3-p15.5

Cytogenetics of cancer

apart from chromosome 11 aberrations, multiple chromosomes are involved in tumour development; promising prognostic indicators in Wilms tumour might be chromosome 1p and 16q aberrations; tther molecular abnormalities associated with an adverse outcome in Wilms tumour are 22q allele loss or P53 aberrations

Other findingsNote in 10-20% of BWS cases, uniparental disomy of chromosome region

11p15 is seen, mostly in a mosaic form

Genes involved and ProteinsGene Name H19

Location 11p15.5 Note imprinted, maternally expressed, untranslated mRNA DNA/RNADescription the human H19 gene is 2.7 kb long and includes 4 small introns;

maternally expressed, paternal imprint ProteinDescription untranslated Expression highly expressed in endodermal and mesodermal embryonic tissues; in

adult brain, only in the pons and globus pallidus; in adult tissues, expression is primarily confined to skeletal and cardiac muscle; other tissues are down-regulated postnatal but re-expressed in tumours that express the gene during embryogenesis

Function putative tumour suppressor; proposed regulatory function for IGF2 expression (under debate)

Mutations


Germinal hypermethylated in 10-20% of sporadic BWS cases; familial transmission unclear yet; loss of imprinting (LOI) can be induced in deletion mouse models

Somatic hypermethylated in 10-20% of sporadic BWS cases mostly somatic events due to UPD in mosaic form; LOI in tumours

11p15.5

Germinal

Somatic

Description

Protein316 amino acids; 32,177 kDa, CDK inhibitory domain, PAPA repeat, conserved C-terminal domain It is expressed in the heart, brain, lung, skeletal muscle, kidney, pancreas and testis; high levels are seen in the placenta, low levels in liver nuclear Summary: Cyclin-dependent kinase inhibitor 1C is a tight-binding inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell

Gene Name IGF2 (insulin-like growth factor 2 (somatomedin A))

Location ProteinDescription 180 amino acids, 20,14 kDa (unprocessed) Expression IGF2 has the highest levels of expression in tissues that are affected by

prenatal overgrowth in BWS; the main source of expression is liver; expression depends on promoter usage; P1 is exclusively active in adult liver, whereas P3 and P4 exert their action in liver prenatal; P2 is only active in certain tumour cell lines

Localisation secreted Function embryonal growth factor, mitogen Homology belongs to the insulin/IGF/relaxin family Mutations

hypomethylated; LOI in sporadic BWS cases; familial transmission unclear yet; BWS phenotype can be induced in igf2 overexpressing mouse models hypomethylated, LOI in sporadic BWS cases; mostly somatic events due to UPD in mosaic form; LOI in tumours

Gene Name CDKN1C (cyclin-dependent kinase inhibitor 1C)

Location 11p15.5 DNA/RNA

1511 bp messenger, preferentially maternally expressed (paternal imprint)

Description

Expression

Localisation Function

proliferation; mutations of CDKN1C are implicated in sporadic


cancers and Beckwith-Wiedemann syndrome suggesting that it is a tumour suppressor candidate; in BWS however, no evidence for tumour association was found p21CIP1 CdK inhibitor gene family

KCNQ1OT1 (KCNQ1 overlapping transcript)

11p15.5

Expression Function

Mutationsaberrant methylation in 50-80% of BWS patients not always 100% (might be due to UPD in some cases); inheritance unclear unclear; there is no association between aberrant methylation and tumour development

Gene NameLocation DNA/RNA

mRNA of 3480 bp, 9 exons, at least 5 splice variants; exon 9 runs antisense of a second gene: ZNF214

Homology MutationsGerminal mostly maternal, nucleotide substitutions, small deletions Somatic CDKN1C mutations are described in tumour formation; mouse mutation-

models reveal part of the BWS phenotype in particular the abdominal-wall defects

Gene NameLocation DNA/RNADescription maternally imprinted gene, > 80 kb RNA Protein

untranslated unknown; it is postulated that KCNQ1OT1 might influence the expression of nearby imprinted genes such as CDKN1C or IGF2/H19

Germinal

Somatic

ZNF215

11p15.4

Description

ProteinDescription 517 amino acids, 60,048 kDa; KRABA domain; similarities to a KRABB

domain; SCAN box; nuclear localisation signal KKKR; 2 x 2 zinc-fingers Expression widely expressed at low levels; expression is highest in testis; splice

variants of ZNF215 show tissue specific expression Localisation nuclear Function putative transcription factor; ZNF215 was cloned from a region

associated with hemihypertrophy, cardiac abnormalities, Wilms tumour and minor BWS features; as such the gene might be responsible for a distinct phenotype in BWS


Homology belongs to the Krueppel family of C2H2-type zinc finger proteins MutationsGerminal

Somatic

various amino acids substitutions found in BWS / hemihypertrophy patients; causal relationship with phenotype unclear in tumours no mutations found so far

External linksOMIM 130650 Orphanet Beckwith-Wiedemann syndrome

BibliographyExtreme cytomegaly of the adrenal fetal cortex, omphalocele, hyperplasia of kidneys and pancreas, and Leydig-cell hyperplasia: Another syndrome?Beckwith J. Western Society for Pediatric Research (abstract) Los Angeles 1963 (November 11).

Wiedemann H.

Complexe malformatif familial avec hernie ombilicale et macroglossie, un "syndrome nouveau".

J Genetica Humane 1964; 13: 223-232. Macroglossia, omphalocele, adrenal cytomegaly, gigantism, and hyperplastic visceromegaly.Beckwith J. Birth Defects 1969; 5: 188-196. Clinical features and natural history of Beckwith-Wiedemann syndrome: presentation of 74 new cases.Elliott M, Bayly R, Cole T, Temple IK, Maher ER. Clin. Genet. 1994; 46, 168-174. Medline 95120892 Multiple genetic loci within 11p15 defined by Beckwith-Wiedemann syndrome rearrangement breakpoints and subchromosomal transferable fragments.Hoovers J, Kalikin L, Johnson L, Alders M, Redeker B, Law D, Bliek J, Steenman M, Benedict M, Wiegant J, Cremer T, Taillon-Miller P, Schlessinger D, Ivens A, Westerveld A, Little P, Mannens M, Feinberg A. Proc Nat Acad Sci USA 1995; 92: 12456-12460. Medline 96109285 The Beckwith-Wiedemann syndrome phenotype and the risk of cancer.Schneid H, Vazquez MP, Vacher C, Gourmelen M, Cabrol S, Le Bouc Y. Med Pediatr Oncol 1997; 28: 411-415. Medline 97288406


Molecular genetics of Wiedemann-Beckwith syndrome.Li M, Squire JA, Weksberg R. Am J Med Genet 1998; 79: 253-259 (review). Medline 98453165 Risk of cancer during the first four years of life in children from the Beckwith-Wiedemann syndrome.DeBaun M, Tucker MA. Registry J Pediatr 1998; 132: 398-400. Medline 98204450 Loss of imprinting of a paternally expressed transcript, with antisnse orentation to KVLQT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor 2 imprinting.Lee MP, DeBaun MR, Mitsuya K, Galonek HL, Brandenburg S, Oshimura M, Feinberg AP. Proc Natl Acad Sci USA 1999; 96: 5203-5208. Medline 99238508 Disruption of a novel imprinted Zinc-finger gene, ZNF215, in the Beckwith-Wiedemann syndrome.Alders M, Ryan A, Hodges M, Bliek J, Feinberg AP, Privitera O, Westerveld A, Little PFR, Mannens MMAM. Am J Hum Genet 2000; 66: 1473-1484. Medline 20311529 Genetics of Beckwith-Wiedemann syndrome associated tumors: Common genetic pathways.Steenman M, Westerveld A, Mannens M. Genes Chromosom Cancer 2000; 28: 1-13 (review). Medline 20204138 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s)

11-2000 Marcel Mannens Written

CitationThis paper should be referenced as such : Mannens M . Beckwith-Wiedemann syndrome. Atlas Genet Cytogenet Oncol Haematol. November 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/BeckwithWiedemannID10037.html





Hereditary breast cancer IdentityNote hereditary or familiar form of breast cancerwith a familiar background Other names � site-specific breast cancer

� familiar breast-ovarian cancer Inheritance � follows an autosomal dominant pattern

� 5-10 % of all breast cancers have hereditary background � hereditary susceptibility for breast cancer has been counted to be 30-40 % of BRCA1 (see below, gene section), 10-30 % of BRCA2, less than 1 % of Tp 53, less than 1 % of PTEN and one third of unknown mutations; frequency of BRCA1 mutation is around 0.2 % in general population, 200 carriers among 100 000 individuals.

ClinicsNote hereditary breast cancer is a heterogenous entity including several

clinical variants Phenotype and clinics

"site specific breast cancer" is characterized by the predominance of breast cancer, while "hereditary breast-ovarian cancer" has neoplasms in both organs � BRCA1 mutation carrier (chromosome 17q12-21) has early age at onset, and lifetime risk for breast cancer 50 % - 85 % and ovarian cancer 15 %-45 %; about 500 different mutations have been reported; possible increased risk of prostate cancer and colon cancer � BRCA2 (chromosome 13q12-13) mutation carrier has risk for breast cancer 30 %-85 %; about 300 different mutations have been reported; it is also associated for male breast cancer (6 %) and ovarian breast cancer (10% -20%); increased risk of prostate, laryngeal cancer and pancreatic cancer. � other genetic conditions associated with increased breast cancer risk are: � Li-Fraumeni syndroma (p53 mutation on chromosome 17p13) is characterized by very early onset of neoplasms, including soft tissue sarcoma, osteosarcoma, brain tumours, leukemia, lung cancer, laryngeal cancer and adrenocorteal cancer.; lifetime risk for cancer: about 90 % for women and 70 % for men � Cowden syndroma (PTEN, 10q23) is a rare type of autosomal dominant inherited condition of multiple hamartomas with increased risk of bilateral breast cancers and thyroid tumours � Muir-Torre Syndroma ( MSH2 , MLH1), with also cancers of the gastro intestinal (GI)-tract, skin, genito urinary (Gu)-system


� Peutz-Jeghers Syndroma, with also abnormal melarin deposits, GI-polyposis, cancers of the GI-tract, uterus, ovary and testis. � Ataxia-teleangiectasia (linked to chromosome 11q21) autosomal recessive disorder with many clinical signs including increased risk for breast cancer; homozygous AT carriers have around 100-fold risk of cancer � one third of familiar breast cancers with hereditary background is still unknown; recent findings indicated that genotyping "BRCA3" locus at 13q and "BRCA2" locus at 2q may lead identifing the next mutations. � breast cancers of BRCA1 and, to lesser extent BRCA2 carriers differ from those of sporadic breast cancers: more high-grade tumours, pleomorphism, a higher mitotic count, less tubule formation, more often steroid receptor negative, DNA-aneuploid and more often higher s-phase fractions.

Treatment � prophylactic bilateral mastectomy (reduces the risk of about 90 %) and/or ovarian ablation. Chemoprevention (antiestrogens, aromataze inhibitors, retinoids) mainly in clinical trials (tamoxifen may reduce the risk about 45 %). � early detection of cancers by screening mammograms (ultrasound) yearly, palpation, transvaginal ultrasound.

Prognosis prognosis is more dependent on extent of the disease at diagnosis than on the hereditary susceptibility

Genes involved and ProteinsNote see also breast cancer

BRCA1

Location

Protein

more than 500 sequence variations of the germline level have been reported

Gene Name

17q21 DNA/RNADescription 22 coding exons spanning over 70 kb of genomic DNA the BRCA1

mRNA has a size of 7.8 kb

Description the corresponding protein has 1863 amino acids, and 190-220 kDa Expression wide Function involved in DNA replication, repair transcriptional activation, cell cycle

progression MutationsGerminal

Gene Name BRCA2

Location 13q12-13


DNA/RNADescription gene spanning more than 17 kb of genomic DNA; the coding sequence

comprisons 26 exons (10 254 nucleotides) ProteinDescription

the corresponding protein has 3 418 amino acid residives (384 kDa) MutationsGerminal more than 300 unique germ-line mutations have been reported

Gene Name P53

Location

ProteinFunction

17p13 DNA/RNADescription 11 exons

gene p53 encodes an ubiquitous nuclear protein involved in the control of genome integrity by preventing cells dividing before DNA damage is repaired

Gene Name PTEN

10q23 Location DNA/RNADescription 9 exons ProteinDescription the PTEN protein (also called MMA1) is an evolutionary conserved dual-

extensive similarity with the cyto-skeletal protein tensin Function tumour suppression since bi allealic inactivations, inactivating germline

mutations are responsible for a cancer prone syndrome MutationsGerminal heterozygeous germline mutations are responsible for the Cowden

disease Gene Name LKB1

Location 19p13 DNA/RNADescription 10 exons spanning 23 kb


ProteinDescription

Function

433 amino acids Expression wide

serine/threonine kinase; tumor suppressor gene Homology heterozygous mutations are responsible for the Peutz-Jeghers

syndrome

Gene Name ATM

Location

66 exons spanning 184 kb

11q22-23 DNA/RNADescription ProteinDescription 3056 amino acids, 350 kDa Function at the cell cycle checkpoint; induces G1 phase arrest

External linksOrphanet Breast cancer, familial

BibliographyCowden syndrome and Lhermitte-Duclos disease in a family: a single genetic syndrome with pleiotropy?

Prophylactic mastectomy for genetic predisposition to breast cancer. The proband´s story.Eeles JWR, Cole T, Taylor R, Lunt P, Baum M.

Hereditary cancer: two hits revisited.

Eng C, Murday V, Seal S, Mohammed S, Hodgson S, Chaudary M, Fentiman I, Ponder B, Eeles R. J Med Genet 1994; 31: 458-461.

Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium.Easton DF, Ford D, Bishop DT. Am J Hum Gen 1995; 56: 265-271.

Clin Oncol 1996; 8: 222-225.

Knudson AG. J Cancer Res Clin Oncol 1996; 122: 135-140. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.


Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, Tucker MA. N Engl J Med 1997; 336: 1401-1408.

The Breast Cancer Linkage Consortium.

Population-based study of risk of breast cancer in carriers of BRCA2 mutation.

The pathology of familiar breast cancer: evidence for differences between breast cancers developing in carriers of BRCA1 mutations, BRCA2 mutations and sporadic cases.

Lancet 1997; 349: 1505-1510. Tamoxifen for prevention of breast cancer: Report of the national surgical adjuvant breast cancer: Report of the national surgical adjuvant breast and bowel project P-1 study.Fisher B, Costantino JP, Wickerholm DI et al. J Natl Cancer Inst 1998; 90: 1371-1388. Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients.Fodor FH, Weston A, Bleiweiss H et al. Am J Hum Genet 1998; 63: 45-51. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families.Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Aranson A, Scherneck S, Peto J, Rabbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M. Am J Hum Genet 1998; 62: 676-689.

Thorlacius S, Struewing JP, Hartge P et al. Lancet 1998; 352: 1337-1339.

Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations.Lakhani SR, Jacquemier J, Sloane JP, Gusterson BA, Anderson TJ, van de Vijver MJ, Farid LM, Venter D, Antoniou A, Storfer-Isser A, Smyth E, Steel CM, Haites N, Scott RJ, Goldgar D, Neuhausen S, Daly PA, Ormiston W, McManus R, Scherneck S, Ponder BA, Ford D, Peto J, Stoppa-Lyonnet D, Easton DF. J Natl Cancer Inst 1999; 90: 1138-1145. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer.Peto J, Collins N, Barfoot R et al. J Natl Cancer Inst 1999; 91: 943-949. Somatic deletions in hereditary breast cancers implicate 13q21 as a putative


novel breast cancer susceptibility locus.Group 1: Kainu T, Juo SHH, Desper R, Schäfferm AA, Gillanders E, Rozenblum E, Freas-Lutz D, Weaver D, Stephan D, Bailey-Wilson J, Kallioniemi O-P, Group 2: Tirkkonen M, Syrjäkoski K, Kuukasjärvi T, Koivisto P, Karhu R, Holli K, Group 3:Aranson A, Johannesdottir G, Bergthorsson J, Johannesdottir H, Egilsson V, Barkardottir RB, Group 4: Johannsson O, Haraldsson K, Sandberg T, Holmberg E, Grönberg H, Olsson H, Borg Å, Group 5: Vehmanen P, Eerola H, Heikkilä P, Pyrhönen S, Nevanlinna H. Proc Natl Acad Sci 2000; 97: 9603-9608. REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s)

11-2000 Kaija Holli Written

CitationThis paper should be referenced as such : Holli K . Hereditary breast cancer. Atlas Genet Cytogenet Oncol Haematol. November 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/HeredBreastCanID10062.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



Variegated aneuploidy related to premature centromere division (PCD) IdentityNote

� it has been proposed that patients with variegated aneuploidy related to PCD are homozygotes for this trait, but in several cases one of the parents do not show elevated frequency of PCD

� the term premature centromere division has also been utilized to describe an unrelated cytogenetic phenomenon, the age related loss of centromeric function in chromosome X � variegated aneuploidy has also been described in patients without PCD and patients with Roberts syndrome

Other names

(Variegated aneuploidy or mosaic aneuploidy) related to (PCD, C-anaphases,premature anaphase, premature chromatid separation or asynchrony of mitotic stages)

Inheritance � only 11 patients known � premature centromere division (PCD) without variegated aneuploidy has been shown to have an autosomal dominant inheritance, with an estimated frequency of 0.1% of the population

� a recessive inheritance with hormonal factors modifying the expression of PCD in a carrier, isodisomy of one chromosome or loss of heterozygosity has been suggested

ClinicsNote patients show a remarkably constant clinical phenotype probably due to

high cellular mortality induced by the aneuploidies; similar clinical findings have also been found in other patients with an expected increased cellular mortality (variegated aneuploidy without PCD and the "ring syndrome")

Phenotype and clinics

the clinical phenotype of the 11 patients described in the literature includes microcephaly (11/11), central nervous system (CNS) anomalies (5/6) with cerebellar defects and migration defects, mental retardation (8/9), prenatal (always noted over 23 weeks of gestation) and postnatal growth retardation (10/10), flat and broad nasal bridge (4/7), apparently low-set ears (5/8), eye abnormalities (8/10), skin abnormalities (3/9) and ambiguous genitalia in male patients (4/6); seizures have been reported in 5 patients; cancer is a major concern in the clinical management of these patients (5/11); birth weight corrected for gestational age ranges from -1.3 to -4.1 SD, birth length from -0.8 to -5.4 SD and OFC from -2.6 to -5.8


Neoplastic risk

the occurrence of Wilms tumor in three patients, rhabdomyosarcoma in two others and acute leukemia in a fifth characterizes this condition as a chromosome instability disorder with a high risk of malignancy; interestingly enough, preferential loss of maternal 11p15.5 chromosome region has been repeatedly reported in Wilms tumor as well as in rhabdomyosarcoma

Prognosis although published data is incomplete, at least 4 patients have died before 2 years of age, a fifth deceased at 42 years and one patient aged 18 month has an advanced, relapsed rhabdomyosarcoma; patient's death had been related to pneumonia (one patient), leukemia (one patient), and Wilms tumor (three cases)

CytogeneticsInborn conditions

� the terms premature centromere division (PCD), C-anaphases, premature anaphase, premature chromatid separation and asynchrony of mitotic stages describe cells in division which have overcome a colchicine-induced metaphase block; the resulting mitotic configuration shows split centromeres and splayed chromatids in all or most of the chromosomes. � control individuals generally show low frequencies of PCD (up to 3% of the mitoses), which seems to have no pathological relevance, but in 0.1% of the population an elevated PCD frequency (>5%) is found in colchicine exposed lymphocyte cultures; this type of PCD shows autosomal dominant inheritance and has traditionally considered to be harmless with the possible exception of some patients with subfertility or repeated abortion. � in few patients high levels of PCD (25- 87%) are found in combination with an increased number of cells with mosaic aneuploidies, microcephaly, mental retardation and a variety of malformations; in these patients, trisomy is by far more frequent than monosomy; trisomies of chromosome 8, 18 and X predominate in lymphocyte cultures and trisomy 2, 7, 12 and 20 predominate in fibroblasts; usually, at least one of the parents shows an elevated PCD frequency (range 12.6-42.5) but not variegated aneuploidy. � high levels of PCD have been reported in skin fibroblasts (althought in at least one case no aneupoidies where found), hair-root, bone marrow and trophoblastic cells of chorionic villi; there is no data of PCD expression in amniocytes but pseudomosaicism of chromosome 7 and 21 has been reported in amniocytes; cord blood chromosome analysis in one case showed PCD and variegated aneuploidies.


cell showing premature centromere division (PCD) phenomenon, with split

centromeres and splayed chromatids in all the chromosomes

analysis of one embryonal rhabdosarcoma showed normal karyotype in cultured cells and extensive aneuploidy with some estructural aberrations in the only two cells obtained from direct harvest

Cytogenetics of cancer

cytogenetic

External linksOMIM 176430 Orphanet Mosaic variegated aneuplody microcephaly syndrome

BibliographyPremature centromere division dominantly inherited in a subfertile family.

Medline 87052989

Gabarron J, Jimenez A, Glover G. Cytogenet Cell Genet. 1986; 43: 69-71.

A mitotic mutant causing non- disjunction in man.Scheres JM JC, Hustinx TWJ, Madam K, Beltman J D, Lindhout D. In: 7h International Congress of Human Genetics. Berlin. 1986; p. 163. abstr. Does "ring syndrome" exist? An analysis of 207 case reports on patients with a ring autosomeKosztolenányi G. Hum Genet .1987; 75: 174- 179. Medline 87135668 Premature centromere division. PCD.: a dominantly inherited cytogenetic anomaly.


Madan K, Lindhout D, Palan A. Hum Genet.1987; 77: 193-196. Medline 88006183

Hum Genet. 1988; 78: 111- 114. (REVIEW)

C- anaphases in lymphocyte cultures versus premature centromere division syndromes.Chamla Y.

Medline 88113657

Mitotic disturbance associated with mosaic aneuploidies.

Medline 90169968

Miller K, Muller W, Winkler L, Hadam M R, Ehrich J H H, Flatz S D. Hum Genet.1990; 84: 361-364.

Mosaic variegated aneuploidy with microcephaly: a new human mitotic mutant?Warburton D, Anyane-Yeboa K, Taterka P, Yu C, Olsen D.

Ann Genet.1991; 34: 287-292. Medline 92231500 C-anaphases: a mitotic variant.Dominguez M, Rivera H. Ann Genet. 1992; 35: 183- 185. Medline 93103259

Mosaic variegated aneuploidy with multiple congenital abnormalities: homozygosity for total premature chromatid separation trait

Medline 98339713

Kajii T, Kawai T, Takumi T, Misu H, Mabuchi O, Takahashi Y, Tachino M, Nihei F, Ikeuchi T. Am J Med Genet. 1998; 78: 245-249.

Syndrome of microcephaly, Dandy Walker malformation, and Wilms tumor caused by mosaic variegated aneuploidy with premature centromere division (PCD): report of a new case and review of the literature.Kawame H, Sugio Y, Fuyama Y, Hayashi Y, Suzuki H, Kurosawa K, Maekawa K. J Hum Genet. 1999; 44: 219- 224. Medline 99357990

Am J Hum Genet.1999; 82: 20- 24.

Child with mosaic variegated aneuploidy and embryonal rhabdomyosarcoma.Limwongse Ch, Schwartz S, Bocian M, Robin N H.

Medline 99113875

Mosaic varie

gated aneuploidies in a newborn with growth retardation and


dismorphic phenotype.

Matsuura S, Ito E, Tauchi H, Komatsu K, Ikeuchi T, Kajii T.

Medline 20349287

D'Agostino A, Calzone R, Poggi V, Zatterale A, Nitsch L. In: European Human Genetics Conference 2000, Amsterdam, p. 80. abstr. Chromosomal instability syndrome with total premature chromatid separation with mosaic variegated aneuploidy is defective in mitotic- spindle checkpoint.

Am J Hum Genet. 2000; 67: 483- 486.

Variegated aneuploidy related to premature centromere division (PCD) is expressed "in vivo" and is a cancer-prone disease.Plaja A, Vendrell T, Smeets D, Sarret E, Gili T, Catalá V, Mediano C, Scheres JMJC.Am J Med Genet. 2000; in press. (REVIEW) REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed


Written Alberto Plaja

CitationThis paper should be referenced as such : Plaja A . Variegated aneuploidy related to premature centromere division (PCD). Atlas Genet Cytogenet Oncol Haematol. November 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/VariegAneuplPCDID10069.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



Hereditary Pancreatic Cancer IdentityOther names familial pancreatic cancer

Inheritance it has been estimated that as many as 10% of pancreatic cancers have a hereditary basis; five genetic syndromes have been identified that are associated with the familial aggregation of pancreatic cancer; these include: � the second breast cancer syndrome (BRCA2), � the familial atypical multiple mole melanoma (FAMMM), � the Peutz-Jeghers Syndrome, � the hereditary pancreatitis and � the hereditary non-polyposis colorectal cancer (HNPCC) syndrome � most kindreds with familial pancreatic cancer, however, do not fall into one of these well-defined syndromes and these are referred to simply as "family pancreatic cancer."

Clinicsa generally accepted definition of familial pancreatic cancer is a kindred in which at least a pair of first-degree relatives (sibling-sibling or parent-child) have been diagnosed with pancreatic cancer; several large registries have been established to define the patterns of inheritance and genetic basis for the familial aggregation of pancreatic cancer in these kindreds; the National Pancreas Tumor Registry (NFPTR) is the largest such registry; over 260 familial pancreatic cancer kindreds have enrolled in this registry and studies of these kindreds has revealed that when followed prospectively, apparently healthy, first-degree relatives of patients with familial pancreatic cancer have an 18-fold increased risk of developing pancreatic cancer; when there are three or more family members with pancreatic cancer in a kindred, the first-degree relatives of the index patient with pancreatic cancer have a 56-fold increased risk of developing pancreatic cancer each of the five clinically recognized syndromes associated with the familial aggregation of pancreatic cancer has its own unique clinical findings

Note

� second breast cancer syndrome: the BRCA2 tumor suppressor gene is located on chromosome 13q and carriers of germline BRCA2 mutations have a significant lifetime risk of developing breast cancer (30-85%) at a young age; they are also at risk for bilateral breast cancer; BRCA2 is also associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer and pancreatic cancer; the


lifetime risk of pancreatic cancer in carriers of germline BRCA2 mutations is approximately 10%; germline BRCA2 mutations are particularly common amongst individuals of Ashkenazi Jewish heritage because of a founder effect

� familial atypical multiple mole melanoma (FAMMM) syndrome has an autosomal dominant mode of transmission; most cases are caused by germline mutations in the p16 tumor suppressor gene on chromosome 9p; individuals affected with FAMMM develop multiple melanocytic nevi, some of which can be atypical; they also are at increased risk of developing melanoma and pancreatic cancer; the lifetime risk of pancreatic cancer in individuals with germline p16 mutations is about 20% � the Peutz-Jeghers Syndrome is inhertied in an autosomal dominant mode; it has recently been shown to be caused by germline mutaitons in the STK11/LKB1 gene on chromosome 19p; individuals with this syndrome typically develop multiple mucocutaneus melanin macules, harmartomatous gastrointestinal polyps and they have an increased risk of developing cancers of the gastrointestinal tract; it has been estimated that the lifetime risk of pancreatic cancer in patient with the Peutz-Jeghers Syndrome is approximately 30% � hereditary pancreatitis has an autosomal dominant mode of transmission; it is caused by germline mutations in the cationic trypsinogen gene (called PRSS1) on chromosome 7q35; affected individuals develop recurrent episodes of pancreatitis at a young age and they have an elevated lifetime risk of developing pancreatic cancers that approaches 40% � the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome is caused by germiline mutations in one of the DNA mismatch repair genes (such as hMLH1 on chromosome 3 p and hMSH2 on chromosome 2p); in addition to colorectal neoplasia, affected family members have an increased risk of developing pancreatic cancer; the pancreatic cancers that arise in patients with HNPCC often have a distinct histologic appearance referred to as "medullary" histology � the ataxia-telangectasia and familial adenomatous polyposis syndromes have also been associated with an increased risk of developing pancreatic cancer, however, these associations are not well-established

Treatment currently, there are no effective methods to screen individuals at-risk for early pancreatic cancer; several studies are underway to examine the effectiveness of endoscopic ultrasound (EUS) in the early detection of pancreatic cancer

Prognosis prognosis will depend on the stage of the disease at diagnosis more than it does on hereditary sysceptibility

Genes involved and ProteinsGene Name BRCA2


Location 13q12 3

Function

more than 300 unique germ-line mutations have been reported; the 6174 delT mutation is particularly common in Jewish subjects acquired mutations in BRCA2 rare in pancreatic cancer

p16

DNA/RNADescription gene spanning more than 70kb of genomic DNA; the coding sequence

comprises 27 exons (11 395 nucleotides) ProteinDescription the corresponding protein has 3 418 amino acid residues (384 kDa)

the Brca2 protein binds to Rad51 and serves as an important co-factor in the Rad51 -dependent DNA repair of double strand breaks; the Brca2 protein may also have transcription activation potential

MutationsGerminal

Somatic

Gene Name

germline mutations are associated with the FAMMM Syndrome virtually all invasive pancreatic carcinomas show inactivation of the p16 gene; forty percent by homozygous deletion, 40% by an intragenic mutation coupled with loss of heterozygocity (LOH) and 15% by hypermethylation of the p16 promoter

STK11

Location 9p21 DNA/RNADescription the coding sequence comprises 3 exons: this locus gives rise to 2

distinct transcripts from different promoters (p16 and p16(ARF)) ProteinDescription the corresponding protein, called cyclin-dependent kinase inhibitor-2A,

has 156 amino acid residues Function cyclin-dependent kinase inhibitor 2A binds to CDK4 and inhibits the

ability of CDK4 to interact with cyclinA thereby inducing a G1 cell cycle arrest

MutationsGerminal Somatic

Gene Name

19p13.3 Location DNA/RNADescription gene Spanning 23kb of genomic DNA, the coding sequence comprises

9 exons (1446bp)


ProteinDescription

Gene Name

Germinal

Gene Name

the corresponding protein has 433 amino acid residues Function serine throeonine protein kinase 11 MutationsGerminal almost all germline mutations are predicted to disrupt the function of the

kinase domain Somatic approximately 4% of sporadic pancreatic cancers have somatic

inactivation of STK11

PRSS1

Location 7q35 DNA/RNADescription the coding sequence comprise 5 exons (800bp) ProteinDescription trypsin, which is active in the pacreas, in inactivated by cleavage;

mutations which abrogate this cleavage site can result in autodigestion and pancreatitis

Mutationsthe arg117-to-his mutation (R117H) is the most common mutation identified to date

hMLH1

Location DNA/RNA

the coding sequence comprises 2484b

Germinal

3p21.3

Description ProteinDescription MLH1 forms a complex with other DNA mismatch repair gene; functions

in DNA mismatch repairs Mutations

one of at least 5 known human mismatch repair genes associated with the hereditary non-polyposis colorectal cancer syndrome: the neoplasms that develop in these patients typically show microsatellite instability

Gene Name hMSH2

Location 2p22-p21 DNA/RNA


Description the MSH2 locus covers approximately 73kb and contains 16 exons ProteinDescription MSH2 functions in DNA mismatch repair

MutationsGerminal one of at least 5 known human mismatch repair genes associated with

the hereditary non-polyposis colorectal cancer syndrome; the neoplasms that develop in these patients typically show microsatellite instability

External linksOMIM 260350 Orphanet Pancreatic carcinoma, familial

Other database National Familial Pancreas Tumor Registry

Other database

The European Registry Of Hereditary Pancreatitis And Familial Pancreatic Cancer

BibliographyGeneralized intestinal polyposis and melanin spots of the oral mucosa, lips and digits.Jeghers HMD, McKusick VAMD, Katz KHMD. N Engl J Med 1949; 241: 992-1005. Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: a family study.Lynch HT, Voorhees GJ, Lanspa S, McGreevy PS, Lynch J. Br J Cancer 1985; 52: 271-273. Increased risk of cancer in the Peutz-Jeghers syndrome.. Giardiello FM, Welsh SB, Hamilton SR, Offerhaus GJA, Gittelsohn AM, Booker SV, Krush AJ, Yardley JH, Luk GD. N Engl J Med 1987; 316: 1511-1514. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma.Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern, SE. Nat Genet 1994; 8: 27-32. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16 INK4 mutations.Goldstein AM, Fraser MC, Struewing JP, Hussussian CJ, Ranade K, Zametkin DP,


Fontaine LS, Organic SM, Dracopoli NC, Clark WH, Tucker MA. N Engl J Med 1995; 333: 970-974. A common mutation in BRCA2 that predisposes to a variety of cancers is found in both Jewish Ashkenazi and non-Jewish individuals.Berman DB, Costalas J, Schultz DC, Grana G, Daly M, Godwin AK. Cancer Res 1996; 56: 3409-3414. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas.Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, Yeo CJ, Jackson CE, Lynch HT, Hruban RH, Kern SE. Cancer Res 1996; 56: 5360-5364. A gene for hereditary pancreatitis maps to chromosome 7q35.Whitcomb DC, Preston RA, Aston CE, Sossenheimer MJ, Barua PS, Zhang Y, Wong-Chong A, White GJ, Wood PG, Gates LK Jr, Ulrich C, Martin SP, Post JC, Ehrlich GD. Gastroenterology 1996; 110: 1975-1980. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich C, Martin SP, Gates LK, Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Ehrlich GD. Nat Genet 1996; 14: 141-145. Hereditary pancreatitis and the risk of pancreatic cancer.Lowenfels AB, Maisonneuve EP, Dimagno YE, Gates LK, Perrault J, Whitcomb DC, and International Hereditary Pancreatitis Study Group. J Natl Cancer Inst 1997; 89: 442-446. Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients.Ozcelik H, Schmocker B, DiNicola N, Shi XH, Langer B, Moore M, Taylor BR, Narod SA, Darlington G, Andrulis IL, Gallinger S, Redston MS. Nat Genet 1997; 16: 17-18. Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells.Abbott DW, Freeman ML, Holt JT. J Natl Cancer Inst 1998; 90: 978-985. Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology: Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+.Goggins M, Offerhaus GJA, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo


CJ, Kern SE, Hruban RH. Am J Pathol 1998; 152: 1501-1507. A serine/threonine kinase gene defective in Peutz Jeghers syndrome.Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Hoglund P, Jarvinen H, Kristo P, Pelin K, Ridanpaa M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MD, de la Chapelle A, Aaltonen LA. Nature 1998; 391: 184-187. Genetics of pancreatic cancer: From genes to families.Hruban RH, Petersen GM, Ha PK, Kern SE.

Familial pancreatic cancer.Hruban RH, Petersen GM, Goggins M, Tersmette AC, Offerhaus GJA, Falatko F, Kern SE. Ann Oncol 1999; 10: S69-S73. (REVIEW). Pancreatic cancer - More familial than you thought.Tascilar M, Tersmette AC, Offerhaus GJA, Hruban RH.

Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers.

Inherited predisposition to pancreatic adenocarcinoma: Role of family history and germ-line p16, BRCA1, and BRCA2 mutations.

Genetic counselin

Surg Oncol Clin N Am 1998; 7: 1-23. (REVIEW). Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase.Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, M¸ller O, Back W, Zimmer M. Nat Genet 1998; 18: 38-43.

Anal Cell Pathol 1999; 19: 105-110. (REVIEW).

Su GH, Hruban RH, Bova GS, Goggins M, Bansal RK, Tang DT, Shekher MC, Westerman A-M, Entius MM, Yeo CJ, Kern SE. Am J Pathol 1999; 154: 1835-1840. Very high risk of cancer in familial Peutz-Jeghers Syndrome.Giardiello FM, Brensinger JD, Tersmette AC, Goodman SN, Petersen GM, Booker SV, Cruz-Correa M, Offerhaus JA. Gastroenterology 2000; 119:1447-1453.

Lal G, Liu G, Schmocker B, Kaurah P, Ozcelik H, Narod SA, Redston M, Gallinger S.Cancer Res 2000; 60: 409-416.

g and testing for germ-line p16 mutations in two pancreatic


cancer-prone families: Case Report.

Gastroenterology 119:1756-1760, 2000.

Am J Pathol 2000; 156: 1641-1651.

Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer.Tersmette AC, Petersen GM, Offerhaus GJA, Falatko FC, Goggins M, Rosenblum E, Wilentz RE, Yeo CJ, Cameron JL, Kern SE, Hruban RH. Clin Cancer Res (In Press).

REVIEW articles

Lynch HT, Brand RE, Lynch JF, Fusaro RM, Smyrk TC, Goggins M, Kern SE.

Genetic, immunohistochemical, and clinical features of medullary carcinomas of the pancreas: A Newly described and characterized entity.Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJA, Hruban RH, Kern SE.

automatic search in PubMed

Last year publications automatic search in PubMed Contributor(s)Written 12-

2000 Ralph H. Hruban, Scott E. Kern

CitationThis paper should be referenced as such : Hruban RH, Kern SE . Hereditary Pancreatic Cancer. Atlas Genet Cytogenet Oncol Haematol. December 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/HeredPancrCanID10068.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology



Li-Fraumeni Syndrome IdentityNote

Inheritance

families with Li-Fraumeni syndrome (LFS) are defined by: a proband with a sarcoma aged under 45 years, with a first degree relative with cancer under 45 years and another first or second degree relative with any cancer under 45 years or a sarcoma at any age autosomal dominant, high penetrance (100% lifetime risk in females, 75% in males)

ClinicsPhenotype and clinics no associated dysmorphologies or abnormalities

Neoplastic risk

very high � the main neoplastic risks are bone, cartilage and soft tissue sarcomas, early-onset female breast cancer, brain and spinal cord tumours, childhood adrenocortical tumours, Wilms' tumour and malignant phyllodes tumours � there is no increased incidence of a number of cancers which occur frequently within the population, such as colorectal, lung, bladder and gynaecological malignancies � some other tumour types occur rarely, but more frequently than expected; these include pancreas, peripheral nervous system, leukaemia and stomach

Genes involved and Proteins

TP53Gene Name

17p13

Description

Function

Location DNA/RNA

11 exons, the first of which is non-coding ProteinDescription p53, a 393 amino acid protein

� p53 is the most commonly mutated gene in human cancers possessing multiple properties; p53 has two major roles � firstly in cell cycle arrest, predominantly in the G1 phase of the cell cycle, but also with a role in G2 and mitotic checkpoints � secondly the induction of apoptosis (programmed cell death)


� both these are induced upon DNA damage, and the response depends on many things including the type of damage and the cell type � p53 is a transcription factor with a central sequence-specific DNA binding domain and a N-terminal transactivation domain; upon DNA damage, the level of p53 increases markedly, and the DNA-binding properties are activated; the levels of p53 are regulated primarily post-transcriptionally (including phosphorylation and acetylation)

MutationsGerminal there are over 200 published reports of germline mutations

� over 75% of families with classic LFS have a germline TP53 mutation � lower proportions of families with some features of LFS have such mutations � children with adrenocortical carcinoma have an extremely high incidence of germline mutations (over 80%) the spectrum of mutations in the germline is superficially the same as somatic mutations, but there are some significant differences

Gene Name hCHK2

Location 22q12.1 DNA/RNADescription 14 exons ProteinDescription a 543 amino acid protein with homology to Saccharomyces cerevisiae

RAD53 and Schizosaccharomyces pombe cds1. Function a protein kinase which is required for DNA damage and replication

checkpoints; CHK2 is phosphorylated by ATM, and in turn can phosphorylate p53 at serine-20; it appears that germline hCHK2 mutations are uncommon in LFS

External linksOMIM 151623 Orphanet Li-Fraumeni syndrome

BibliographySoft-tissue sarcomas, breast cancer and other neoplasms: a familial syndrome?Li FP, Fraumeni JF. Ann Intern Med 1969; 71: 747-752. A cancer family syndrome in twenty-four kindreds.Li FP, Fraumeni JF, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW. Cancer Res 1988; 48: 5358-5362.


Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.Malkin D, Li FP, Strong LC, Fraumeni JF, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, Friend SH. Science 1990; 250: 1233-1238. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families.Birch JM, Hartley AL, Tricker KJ, Prosser J, Condie A, Kelsey AM, Harris M, Morris Jones PH, Binchy A, Crowther D, Craft AW, Eden OB, Evans DGR, Thompson E, Mann JR, Martin J, Mitchell ELD, Santibanez-Koref MF. Cancer Res 1994; 54: 1298-1304. Li-Fraumeni syndrome - a molecular and clinical review.Varley JM, Evans DGR, Birch JM. Br J Cancer 1997; 76: 1-14. Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families.Varley JM, McGown G, Thorncroft M., Santibanez-Koref MF, Kelsey AM, Tricker KJ, Evans DGR, Birch JM. Cancer Res 1997; 57: 3245-3252. Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni Syndrome.Birch JM, Blair V, Kelsey AM, Evans DGR, Harris M, Tricker KJ, Varley JM. Oncogene 1998; 17: 1061-1068. Heterozygous germ line hCHK2 mutations in Li-Fraumeni Syndrome.Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DCR, Shannon KE, Lubratovich M, Verselis SJ, Isselbacher KJ, Fraumeni JF, Birch J., Li FP, Garber JE, Haber DA. Science 1999; 286: 2528-2531. Are there low penetrance TP53 alleles? Evidence from childhood adrenocortical tumors.Varley JM, McGown G, Thorncroft M., James LA, Margison GP, Forster G, Evans DGR, Harris M, Kelsey AM, Birch JM. Am J Hum Genet 1999; 65: 995-1006. p53 germline mutations in childhood cancers and cancer risk for carrier individuals.Chompret A, Brugieres L, Ronsin M, Gardes M, Dessarps-Freichey F, Abel A, Hua D, Ligot L, Dondon M-G, Bressac de Paillerets B, Frebourg T, Lemerle J, Bonaiti-Pellie C, Feunteun J. Br J Cancer 2000; 82: 1932-1937.


REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s)

12-2000 Jenny M Varley Written

CitationThis paper should be referenced as such : Varley JM . Li-Fraumeni Syndrome. Atlas Genet Cytogenet Oncol Haematol. December 2000 . URL : http://www.infobiogen.fr/services/chromcancer/Tumors/LiFraumeniID10011.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology


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