ZIA CP010190 - 10374 (ZIA) | |||
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Title | Dyskeratosis Congenita | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Savage, Sharon | NCI Program Director | N/A |
Cancer Activity | N/A | Division | DCEG |
Funded Amount | $406,613 | Project Dates | 01/19/2006 - 00/00/0000 |
Fiscal Year | 2015 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Biochemical Epidemiology (45.0%) Cancer (100.0%) |
Colon/Rectum (10.0%) Leukemia (20.0%) Buccal Cavity (20.0%) Head and Neck (40.0%) Pharynx (20.0%) |
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Research Type | |||
Endogenous Factors in the Origin and Cause of Cancer Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors |
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Abstract | |||
Comprehensive clinical and molecular evaluations of patients with dyskeratosis congenita (DC) and their family members are conducted to better understand the etiology of this cancer-prone telomere biology disorder. DC is an inherited bone marrow failure syndrome characterized by abnormal nails, lacy skin pigmentation, oral leukoplakia, very short telomeres, and significantly elevated risks of cancer. This project developed the only clinical diagnostic test of DC: telomere length measurement by flow cytometry with in situ hybridization (flow FISH). DC is inherited in X-linked, autosomal dominant and autosomal recessive manners. We have discovered four novel causes of DC: (1) Germline mutations in TINF2 provided the first evidence that disruption of the shelterin protein protection complex can cause human disease; (2) DC-causing mutations in WRAP53 were first proof that mislocalization of telomerase could cause human illness; (3) Exome sequencing discovered mutations in the helicase and telomere biology gene RTEL1; and (4) We found germline mutations in a second shelterin component, TPP1 (encoded by ACD), as caused of DC. All patients with DC are evaluated to identify the genetic cause. Our clinical and molecular studies of expanded prior notions of the DC phenotype. The DC Biospecimen Repository has catalyzed multiple collaborative studies with intramural and extramural scientists. For example, these biospecimens were the reagents used to identify that undifferentiated induced pluripotent stem cells accurately recapitulate features of a human stem cell disease (DC), and uncovered novel functional insights of the affected pathways. We worked with the DC Outreach family support group to create the first edition of DC Clinical Care Guidelines. Ongoing clinical and genomic studies will yield insight into telomere biology and improvements in patient care. |