Genetic risk in sarcoma

INTERNATIONAL SARCOMAKINDRED STUDY

ISKS Global

PARTICIPANT

INDIATata Memorial

Hosp

FRANCECentre Claude

Berard

USAHuntsman Cancer Inst

UKMarsden & UCLH

AUSTRALIAPeterMac

Royal Prince AlfredPrince of Wales

Princess AlexandraWesley

Royal AdelaideHollywood Private

CENTRALBiospecimens

LaboratoryDatabase

ISKS GLOBAL STEERING COMMITTEE

BiospecimensLaboratoryDatabase

APPROVED PROJECTS

CANADAVancouver Hosp

NZChristchurch Hosp

BiospecimensLaboratoryDatabase

BiospecimensLaboratoryDatabase

BiospecimensLaboratoryDatabase

BiospecimensLaboratoryDatabase

Local Study Centres

Global Study Centre

ISKS

ISKS families 645 families

207 no family history, 51 uninformative

387 families with cancer historyTP53 related syndromes

9 Classic Li Fraumeni Syndrome58 Chompret LFL19 Birch LFL279 Eeles LFL

Other sarcoma related syndromes1 familial schwannomatosis1 neurofibromatosis2 Gorlin’s syndrome15 other striking pedigrees

Other cancer syndromes1 breast cancer, 2 colorectal cancer

ATM

NBN

RAD50

MRE11A

BRCA1 PALB2

BRCA2 BRIP1

RAD51FANCI/D2

TP53

FANCA-C/E-G/L/M

CHEK2

37/105 (27%) patients carrying 50 cancer predisposition alleles

Screening for heritable cancer genes in sarcoma

Screening for heritable cancer genes in sarcoma

ATM/ATR

NBN

RAD50

MRE11A

BRCA1 PALB2BRIP1BARD1

BRCA2

RAD51FANCI/D2

TP53

FANCA-C/E-G/L/M

CHEK2

6/106

2/106

(19/580)7/106

2/106

38/106 (27%) patients carrying 50 cancer predisposition alleles

1/1062/106

2/106

(0)

(0)

(0)

(0)

TP53 wild-type by MLPA and HRM/Sequencing

TP53 wild-type by MLPA and HRM/Sequencing

* *

*

*

* *

Whole exome sequencing

Genes of interestAffected

Genes of interestAffected

Genes of interestAffected

Sept 2007

Feb 2008

Comparison of the germ cell tumor and the myelodysplasia

JNCI, 1990, 82:221

NEJM, 1990, 322:1425

Clonal i(12p) in both mediastinal GCT and leukemia

Co-expression in leukemic cells of cytokeratin and monocytic markers

DNA Ligase 1• K #2: somatic mutation in LIG1 (T311M, Condel/PolyPhen2 pathogenic)

– Retention of paternal LOF allele (V349M)

• Functions in DNA replication and the base excision repair process– Neil2 involved in BER– Interacts physically with Nbn

• Mutations in LIG1 result in immunodeficiency and increased sensitivity to DNA-damaging agents

• Associated with increased cancer risk– Compound heterozygoyte died of lymphoma age 19– Variants associated with lung cancer risk

• Gene targeting in mice– Required for development– Associated with anemia

Osteoporosis

Rainbows for Kate Foundation

ISKS participants and families

ISKS Australia Steering Committee

ISKS Global Steering Committee

ISKS AustraliaMandy BallingerJess McDonaldKim RiddellBelinda ZielonyJasmine MarKate CroughKate Mahendran

kConFab/ISKS RNsAllison WichtVicki Fennelly

kConFabHeather ThorneEveline NiedermayrLinda WilliamsLana DjandjgavaCarla Osinski

AcknowledgementsPeter MacPaul JamesGillian MitchellMary-Anne Young

Ella ThompsonIan Campbell

Richard Tothill

Maria DoyleJason EllulJason Li

RUNESRapid Understanding of Nucleotide variant Effect Software

STEPHEN KINGSMORE, CENTER FOR PEDIATRIC GENOMIC MEDICINEKANSAS CHILDREN’S MERCY HOSPITAL

Novelty

ENSEMBL

HGMD

dbSNP

Splice effect

ACMG category

Consolidate

Translation impact

Affected genes/transcripts/proteinsNCBI gene

Reference and variant codonsReference and variant AA

HGVS nomenclatureSIFT/POLYPHEN2/BLOSUM/Condel

dbSNP rsID/MAFClinVar cross referenceHGMD cross reference

Splicing/translational effectOMIM cross reference

FrameshiftDomain mapping

Mutations cross referenceMouse Genome DatabaseDECIPHER cross reference

ACMG classification

Category Description Criteria1 Previously reported and recognized

causeHGMD variant disease mutantdbSNP pathogenic clinical significance

2 Novel, pathogenic Loss of initiation, premature or disrupted STOP, whole gene deletion, frameshift, essential splice disruption

3 Novel, may be pathogenic Non-synonymous, in-frame indel, polypyrimidine tract disruption, other splice site variants

4 Novel, probably not pathogenic All variants not in categories 1-3, synonymous, dbSNP MAF>0.02

5 Known neutral -

6 Association with disease, but not expected to be pathogenic

-

Maternal

18

Paternal

1514 16 2616

Neither

114 16

Both(het)

299 2

None homozygous

Nijmegen Breakage Syndrome

Autosomal recessive Fanconi anemia phenotype• Radiosensitivity• Cancer predisposition

-50% incidence <15 years-lymphoid malignancies -brain tumors-rhabdomyosarcoma