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Dyskeratosis Congenita 101 Sharon A. Savage, M.D. Chief, Clinical Genetics Branch Clinical Director, Division of Cancer Epidemiology & Genetics Camp Sunshine September 2018

Dyskeratosis Congenita 101 - Team Telomere...Dyskeratosis Congenita –connecting telomere biology with human disease • Germline mutations in dyskerin (DKC1) found in X-linked recessive

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  • Dyskeratosis Congenita 101

    Sharon A. Savage, M.D.

    Chief, Clinical Genetics Branch

    Clinical Director, Division of Cancer Epidemiology & Genetics

    Camp SunshineSeptember 2018

  • 2012

    2016

  • Dyskeratosis Congenita – early descriptions

    Year Author(s) Reference

    1906 Zinsser, F Atrophia Cutis Reticularis cum Pigmentatione, Dystrophia Unguium et Leukoplakia oris, Ikonogr Derm (Kioto), p 219

    1910 Engman, MF, Sr A Unique Case of Reticular Pigmentation of the Skin with Atrophy, Society Transactions, Arch Derm Syph 13:685

    1930Cole, HN, Rauschkolb JE, and Toomey J

    Dyskeratosis Congenita with Pigmentation, Dystrophia Unguis, and Leukokeratosis Oris, Arch Derm Syph 21:71

  • Archives of DermatologyVol 88, Sept. 1963

  • People with telomere biology disorders may face multiple medical problems

    Remember:Ø Everyone is differentØ These problems don’t

    happen to everyoneØ Things change with ageØ We learn more everyday

    and always

  • Diagnostic Triad 1. Dysplastic Nails

  • Diagnostic Triad 2. Skin pigmentation

  • Diagnostic Triad 3. Oral leukoplakia

  • Bone marrow failureFailure to produce enough blood cells

    LeukemiaCancer of the blood forming cells

    Myelodysplastic syndromeAbnormal looking blood cells associated

    with low numbers and leukemia risk

    Hematopoietic (blood) system

  • Respiratory systemHead and neck

    squamous cell cancer

    Pulmonary fibrosis

    Pulmonary arterio-venous malformations

    (AVMs)Abnormal blood vessel

    formation in lungs

  • Gastrointestinal (GI) system

    Liver diseaseFibrosis and/or abnormal blood vessel

    connections between liver, spleen, and/or lungsBleeding in stomach

    or intestinesPoor absorption of food

    malabsorption

    Esophageal stenosisNarrowing of the esophagus

    Ano-genital cancer

  • Genitourinary system

    Narrowing of the urethraUrethral stenosis

  • Nervous system Small headmicrocephaly

    Small cerebellumBalance problems

    Developmental delay

    Psychiatric illnesses

    Stay tuned for more information in Sonia Bhala’s presentation

  • Skeletal system

    Avascular necrosis of shoulders or hipsLow bone density

    Osteopenia or osteoporosis

    Fractures

  • Eye-related complications

    Tear duct narrowing

    Abnormal eyelash growth

    Tsilou et al, Ophthalmology 2010;117(3):615-22

    Abnormal blood vessels

    in retina

  • What’s in a name?

    • Zinsser – Cole – Engman syndrome• Dyskeratosis Congenita• Hoyeraal Hreidarsson syndrome• Revesz syndrome• Coats plus• Aplastic anemia• Familial pulmonary fibrosis• Familial liver fibrosis

    Telomere Biology Disorder

  • Traditional DC diagnosis: Diagnostic Triad or 1 of the triad, + BMF + 2 other

    findings, Vulliamy et al, Blood, 2006, 107(7):2680-5

    How are these disorders connected?

  • A Classic DC Family

    Dysplastic nails at 15BMF at 17Died at 32 of BMF

    BMF, bone marrow failure

    Dysplastic nails, abnormal skin pigmentation, oral leukoplakia, mild BMF at 13, microcephaly

    Severe BMF at 4Abnormal skin & nails, oral leukoplakia, cerebellar hypoplasia

    Mild BMF at 2, microcephaly

  • Dyskeratosis Congenita – connecting telomere biology with human disease• Germline mutations in dyskerin (DKC1) found in X-linked recessive DC

    • Heiss et al, Nature Genet 1998

    • Dyskerin (DKC1) associates with H/ACA small nucleolar RNAs and hTr (human telomerase RNA, TERC)

    • DKC1 mutant patient-derived cells have low telomerase, very short telomeres• Mitchell and Collins, Nature 1999

    • Accounted for ~20% of DC at the time DKC1

  • What are telomeres?

    • Barbara McClintock:• Maize chromosomes stuck together after exposure to X-rays

    • Something normally protects chromosome ends from this fate

    • Hermann Muller:• Greek: “telos” = end

    “meros” = part

    Reviewed in de Aguiar-Perecin et al., Genet Mol Biol 2000

  • Telomeres are in algae, humans, and everything in between

    Photo: Dr. Peter Lansdorp

  • Molecular structure of telomeres

    • Repeats of DNA bases (TTAGGG)n form single-strand overhang• Single-strand region gets folded over and tucked in

    Telomere

    TTAGGGTTAGGG(TTAGGG)nTTAGGG-3’AATCCC-5’

  • PARNPCNAHistones

    SIRT1

    XRCC6

    EXO1 TERRA

    ATM/ATRCHK1/CHK2

    p53p21

    BRCA1

    Telomeres are protected/regulated by a complex network of proteins

  • Why do we need telomeres?

    DNA damage is a constant threat. Telomeres help keep chromosome ends stable

    cellular replication ultra-violet light chemicals metabolism

  • Why do we need telomeres?

    • Two types of DNA ends:• DNA breaks• Normal ends of chromosome

    • What happens if the cell can’t tell the difference?

    Repair

    Repair

    Repair of a DNA break

    “Repair” of a normal end:

  • Telomeres protect DNA ends from being recognized as DNA damage, and “repaired”

    Repair of a DNA break:

    Repair

    Repair

    NO “repair” of a normal end:

  • Why do we need telomeres?

    They give a limit to the number of times cells can divide, which can limit accumulation of DNA damage

    # Cell divisions

    Telo

    mer

    e le

    ngth

    Senescence(cells with short telomeres stop dividing)

  • Telomeres get shorter as we ageNormal Lymphocytes

    0.0

    2.0

    4.0

    6.0

    8.0

    10.0

    12.0

    14.0

    0 20 40 60 80 100

    Age, years

    Telo

    mer

    e Le

    ngth

    , kb

    1%ile10%ile50%ile90%ile99%ile

    Baerlocher and Lansdorp, Methods Cell Biol 2004Alter et al, Blood 2007

  • Why do telomeres shorten?

    • End Replication Problem* - DNA replication machinery can’t fully copy the ends of DNA

    *Watson, 1972; Olovnikov, 1973

    Shoelace image: Elizabeth Blackburn, PhD, Nobel Lecture 2009

    • Susceptibility to DNA damage

  • Without functional telomeres, chromosome ends can fuse. This causes massive genetic instability

    Okamoto et al., Nature 2013

    Normal telomeres in mouse cells Telomeres missing a critical protein component (TRF2)

  • 31

    Telomeres: Dual Roles in Cancer Development

    Cell divisionTelomere shortening

    Continued cell division with chromosomal abnormalities

    and genomic instability

    shortening

    lengthening Longer telomeres permit more cell divisions and accumulation

    of somatic mutations

  • Development of the Diagnostic Test for DCWhite blood cell flow-FISH Telomere Length

    Alter et al, Haematologica 2012;97(3):353-9Alter et al. Blood 2007;110(5):1439-1447

    Lymphocyte telomeres 95% sensitive and

    specific

    0

    2

    4

    6

    8

    10

    12

    14

    0 20 40 60 80 100

    Telo

    mer

    e Le

    ngth

    , kb

    Age, years

    LymphocytesLymphocytes

    0.0

    2.0

    4.0

    6.0

    8.0

    10.0

    12.0

    14.0

    0 20 40 60 80 100

    Age, years

    Telo

    mer

    e Le

    ngth

    , kb

    DCHHRSSilentDC Rels

    Lymphocytes

    0.0

    2.0

    4.0

    6.0

    8.0

    10.0

    12.0

    14.0

    0 20 40 60 80 100

    Age, years

    Telo

    mer

    e Le

    ngth

    , kb

    DCHHRSSilentDC Rels

    99th %ile90th %ile50th %ile10th %ile1st %ile

    Lymphocytes

    0.0

    2.0

    4.0

    6.0

    8.0

    10.0

    12.0

    14.0

    0 20 40 60 80 100

    Age, years

    Telo

    mer

    e Le

    ngth

    , kb

    DCHHRSSilentDC Rels

  • DC-related Telomere Biology Disorders:Earlier onset, distinct complications

    • Hoyeraal Hreidarsson (HH) Syndrome• Cerebellar hypoplasia• IUGR• Immune Deficiency

    • Revesz Syndrome• Bilateral exudative retinopathy• Intracranial calcifications• IUGR

  • DC-related Telomere Biology Disorders:Earlier onset, distinct complications

    • Coats Plus/CRMCC• Retinal telangiectasias• Exudative retinopathy• Intracranial calcifications and/or cysts• Leukodystrophy• GI vascular ectasias• Osteopenia, fractures, poor bone healing

    Anderson et al, Nature Genetics 2012

  • 35

    DC-related Telomere Biology Disorders:Later onset, fewer complications

    • Apparently isolated disease• Pulmonary fibrosis• Aplastic Anemia (bone marrow failure)• Liver disease• Head and neck squamous cell carcinoma

    • Classic features of DC may not be present• Family history may not be present

    Leukemia,60 Thrombocytopenia,cirrhosis,38

    Grayhair,23SAA,33Diedat47,HSCTcomplications

    SAA,12Naildystrophy,grayhair,teens

    Mutationcarrier

    Normal Lymphocytes

    0.0

    2.0

    4.0

    6.0

    8.0

    10.0

    12.0

    14.0

    0 20 40 60 80 100

    Age, years

    Telo

    mer

    e Le

    ngth

    , kb

    1%ile10%ile50%ile90%ile99%ile

    proband maternalgrandmother

  • What causes telomere biology disorders?• Genetic changes in genes critical in telomere biology• 14 genes associated with TBDs, to date, account for ~75% of patients• Different genes are associated with certain complications

    DKC1

    TERC

    TERT

    NHP2

    NOP10NAF1

    TCAB1

    PARN

    CTC1STN1

    TIN2TPP1

    POT1

    RTEL1

    Details coming up next in Ann Carr’s talk

  • Acknowledgements

    NCI’s IBMFS and Telomere Molecular Epidemiology teams

    Blanche Alter, MD, MPHNeelam Giri, MDLisa Leathwood, RNAnn Carr, CGCLisa Mirabello, PhDShahinaz Gadalla MD, PhDPayal Khincha, MDLisa McReynolds, MD, PhDSonia BhalaAshley Thompson

    Clinical Care Consortium of Telomere-Associated Ailments

    S. Agarwal, HarvardA. Bertuch, BaylorJ. Tolar, Univ MinnesotaF. Boulad, MSKCCK. Myers, Cincinnati

    Functional StudiesS. Artandi: Stanford UniversityA. Bertuch: Baylor College of MedicineT. de Lange: Rockefeller UniversityY. Liu: NIAC. Keegan: University of MichiganP. Lansdorp: University of British ColumbiaJ.K. Nadakumar: University of MichiganJ. Petrini, Memorial Sloan KetteringS. Smith: New York UniversityJ. Wong: University of British ColumbiaAnd many more…

    EpidemiologyI. De Vivo: HarvardR. Hayes: NYUM. Alavanja: NCIL. Hou: NorthwesternA. Aviv: UMDNJ

    Telomere Length Flow-FISHP. Lansdorp, Univ

    British ColumbiaG. Baerlocher,

    University Bern

    NCI Cancer Genomics Research Laboratory

    www.marrowfailure.cancer.gov

    Team Telomere