ZIA CP010190-10374 (ZIA) | |||
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Title | Dyskeratosis Congenita | ||
Institution | NCI, Bethesda, Ma | ||
Principal Investigator | Savage, Sharon | NCI Program Director | N/A |
Cancer Activity | N/A | Division | DCEG |
Funded Amount | $487,156 | Project Dates | 01/19/2006 - N/A |
Fiscal Year | 2011 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Biochemical Epidemiology (45.0%) Cancer (100.0%) |
Buccal Cavity (20.0%) Colon/Rectum (10.0%) Leukemia (20.0%) 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 being conducted to better understand the role of telomere biology defects in this 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. There are multiple modes of inheritance (<i>e.g.</i> X-linked, autosomal dominant and autosomal recessive). We identified a new gene which causes autosomal dominant DC, <i>TINF2</i>, which is a component of the shelterin telomere protection complex. Families with DC are evaluated for mutations in the known DC genes, <i>TINF2, DKC1, TERC, TERT, NOP10</i>, and <i>NHP2</i>. Approximately 17% have <i>TINF2</i>, 20% <i>DKC1</i>, 6% <i>TERC</i>, 8% <i>TERT</i>, and no mutations <i>NOP10</i> or <i>NHP2</i> have been identified. <BR>Through a candidate gene approach we discovered that compound heterozygous mutations in TCAB1 (gene name <i>WRAP53</i>) cause DC. Our collaboration with Stanford University showed that these mutations cause disruption of telomerase trafficking. We sequenced the other five shelterin genes (<i>ACD, POT1, TERF1, TERF2, TERF2IP</i>, and <i>TINF2</i>) in our patients but did not identify disease causing mutations. Ongoing work includes use of next-generation sequencing technologies to identify the genetic causes of DC in mutation-negative families. <BR>We evaluated the role of methylation on telomere length (TL) in patients with DC and their mutation-negative relatives. That study suggests that the relationship between TL and subtelomeric or LINE-1 methylation is different based on the presence of DC-associated mutations. <BR>Numerous extramural and intramural collaborations are underway to better understand the molecular consequences of mutations in telomere biology genes and studies of the clinical features of DC are ongoing. |