dyskeratosis congenita 101 - team telomere...dyskeratosis congenita –connecting telomere biology...
TRANSCRIPT
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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
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2012
2016
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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
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Archives of DermatologyVol 88, Sept. 1963
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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
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Diagnostic Triad 1. Dysplastic Nails
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Diagnostic Triad 2. Skin pigmentation
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Diagnostic Triad 3. Oral leukoplakia
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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
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Respiratory systemHead and neck
squamous cell cancer
Pulmonary fibrosis
Pulmonary arterio-venous malformations
(AVMs)Abnormal blood vessel
formation in lungs
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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
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Genitourinary system
Narrowing of the urethraUrethral stenosis
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Nervous system Small headmicrocephaly
Small cerebellumBalance problems
Developmental delay
Psychiatric illnesses
Stay tuned for more information in Sonia Bhala’s presentation
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Skeletal system
Avascular necrosis of shoulders or hipsLow bone density
Osteopenia or osteoporosis
Fractures
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Eye-related complications
Tear duct narrowing
Abnormal eyelash growth
Tsilou et al, Ophthalmology 2010;117(3):615-22
Abnormal blood vessels
in retina
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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
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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?
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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
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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
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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
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Telomeres are in algae, humans, and everything in between
Photo: Dr. Peter Lansdorp
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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’
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PARNPCNAHistones
SIRT1
XRCC6
EXO1 TERRA
ATM/ATRCHK1/CHK2
p53p21
BRCA1
Telomeres are protected/regulated by a complex network of proteins
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Why do we need telomeres?
DNA damage is a constant threat. Telomeres help keep chromosome ends stable
cellular replication ultra-violet light chemicals metabolism
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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:
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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:
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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)
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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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