The Dyskeratosis congenita (DC) [CAS 10374] study provides comprehensive clinical and molecular evaluations to patients with DC and their family members, to better understand the role of telomere biology defects in this disorder. DC is an inherited bone marrow failure syndrome (IBMFS) characterized by abnormal nails, lacey reticular pigmentation, oral leukoplakia, very short telomeres, and significantly elevated risks of aplastic anemia and cancer. Family pedigrees in DC indicate that there are multiple modes of inheritance (e.g. X-linked, autosomal dominant and autosomal recessive), although many cases are sporadic (i.e., lack a family history). We identified TINF2 as a new gene which causes autosomal dominant DC;it is a component of the shelterin complex of telomere protection proteins. All families with DC enrolled in the NCIs IBMFS study are evaluated for mutations in the known DC genes: TINF2, DKC1, TERC, TERT, NOLA2, and NOLA3. In our cohort of families, the proportion positive for these genes are 28%, 17%, 10%, 7%, 0% and 0%, respectively. Approximately 40% of our patients remain molecularly uncharacterized. These families have been used to demonstrate that very short telomeres (by Flow-FISH) in peripheral blood leukocyte subsets comprise a diagnostic abnormality for this disorder. Analysis of the cancers in these families demonstrates a pattern that is strikingly similar to that observed in Fanconi anemia (i.e., MDS, AML, squamous cell cancers of the head/neck and anorectal cancers). Candidate gene sequencing in the molecularly uncharacterized patients is ongoing. We have recently identified a new gene that appears to cause DC;functional characterization of the mutations underway. We are also exploring several new hypotheses related to DC pathogenesis, including epigenetic gene regulation and chromosomal abnormalities. Detailed characterization of the clinical phenotype and medical complications is ongoing. We are analyzing Telomere Length in Target Tissues [CAS 10373] in a series of methodological studies that seeks to clarify intra-individual variability in telomere length, with the ultimate goal being improved understanding of comparability when different cell types and methods of telomere length determination are employed. Epidemiologic studies typically use DNA isolated from either blood or buccal cells, yet direct comparisons of telomere length in blood and buccal cell DNA have not been published. It is important to understand how telomere lengths measured in commonly-used specimens (blood and buccal cells) compare with each other and with telomere lengths in tissues at risk of cancer development. Since telomere length measurement by Q-PCR and flow-FISH are becoming more widely used, it is also important to understand the intra-individual comparability of these techniques. We have evaluated intra- and inter-individual variation in telomere length in specimen trios (blood, buccal cell and fibroblast DNA) from subjects enrolled in the IBMFS study. A manuscript, which shows that telomere length is correlated in these individuals, is nearing submission. This methodological study seeks to determine whether or not telomere length measured in different tissue types can be combined in future studies. It will form the basis for larger epidemiologic studies of telomere length as a risk factor for cancer and other illnesses. We are investigating Telomere Length as a Risk Factor for Various Cancers [CAS 10371].(1) Prostate cancer: We evaluated telomere length as a prostate cancer risk factor in the PLCO cohort. A statistically significant association between prostate cancer risk and telomere length was not identified, but positive associations were found between telomere length and healthy lifestyle parameters (report published).(2) Ovarian Cancer: Our case-control study of ovarian cancer in Poland showed that leukocyte telomeres were strongly associated with high-grade serous ovarian adenocarcinoma (mauscript in press). A follow-up study employing a larger sample size is underway.(3) Osteosarcoma: Data are currently being analyzed on telomere length in leukocytes from osteosarcoma cases and controls. We are also evaluating the role of SNPs in telomere biology genes in this study.Collaborative studies of telomere length as a risk factor in glioma, pancreatic cancer, and pesticide exposures are ongoing. (4) Genetic Variants That Correlate With Telomere Length are being evaluated utilizing data derived from the NCI CGEMS genome-wide association studies of prostate and breast cancer. Single nucleotide polymorphisms (SNPs) in genes important in telomere biology were evaluated and potential candidates associated with telomere length were identified. We are also collaborating with Harvard on a genome-wide association study of telomere length which utilizes the same sample set.Population Genetics of Telomere Genes [CAS 10372]: We have previously shown that nucleotide diversity is low for critical proteins in the telomere maintenance pathway when compared with other types of genes, and that these genes are highly-conserved between species. Because these genes appear to be under evolutionary constraint, it is possible that germ-line genetic variation (i.e., single nucleotide polymorphisms, SNPs) in these genes could be significant risk factors for cancer or other diseases.The present study is evaluating genetic variation in 37 telomere biology genes from 1000 individuals among 53 worldwide populations - Africa, the Middle East, Europe, Central/South (C/S) Asia, East Asia, Oceania, and the Americas. A set of comparison genes from different functional pathways is being created. This study will provide insight into the evolutionary history of these genes, clarify variants which may have potential functional implications, and allow for tailored, evidence-based SNP selection in future genetic association studies
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