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 have discovered two 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. All families with DC enrolled in the NCIs IBMFS study are evaluated for mutations in the known DC genes: TINF2, DKC1, TERC, TERT, NOP10, NHP2, and WRAP53.. All participants in the DC cohort are evaluated for mutations in the DC-associated genes. However, nearly 50% of our patients are mutation-negative. Our ongoing work includes use of next-generation sequencing technologies to identify the genetic causes of DC in mutation-negative families. Our DC studies 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). The DC Biospecimen Repository is a rich resource used to understand the molecular consequences of telomere biology abnormalities. 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. Telomere Length in Target Tissues [CAS 10373] is now closed. It evaluated intra-individual telomere length measured by QPCR of DNA derived from blood, buccal cells, and fibroblasts from IBMFS patients as well as the correlation between flow-FISH and QPCR. It found that in general, fibroblast telomeres were longer than blood or buccal cell telomeres but that there was significant intra-individual correlation between tissue types. This pilot study forms the basis for larger methodological studies of telomere biology and cancer risk. We are also investigating Telomere Length as Cancer Risk Factor [CAS 10371]. Numerous studies suggest that short surrogate tissue TL is a cancer risk factor. Our previous case-control studies found that short telomeres are associated with increased risk of ovarian and gastric cancer. However, our cohort study of TL and prostate cancer did not find the same association. Our meta-analysis on the association between TL in surrogate tissues and cancer risk which suggests short TL and overall cancer are associated but this may be driven by stronger effects in specific cancers. The ORs derived from retrospective studies were much higher than for prospective studies (2.9 versus 1.16), which suggests reverse causation bias and possible contribution of cancer therapy prior to sample collection. Study heterogeneity and minimal or no data on certain cancer sites were also limitations of these analyses. Ongoing work includes many collaborative studies of TL and cancer designed to 1) determine if TL is associated with risk of specific cancers or cancer-related outcomes, 2) determine differences in TL and cancer associations in case-control versus cohort studies, and 3) use these studies as building blocks for germline (i.e., surrogate) and somatic tissue studies aimed at better understandingthe contribution of telomere biology to cancer etiology Genetic Variants That Correlate With Telomere Length [CAS 10371] have been evaluated through analyses of SNP data derived from the NCI CGEMS GWAS of prostate and breast cancer. We found that 13 SNPs from 4 genes were associated with TL. We also collaborated with Harvard University on a genome-wide association study (GWAS) of TL. That study confirmed a SNP in TERC as associated with TL, but, similar to other studies, did not find strong associations between SNPs at other sites and TL. A new project, Telomere length after HSCT in patients with acquired severe aplastic anemia [CAS 10508] was initiated which seeks to understand the role of telomere biology in outcomes after hematopoictic stem cell transplant (HSCT) for acquired severe aplastic anemia (SAA). Pre-transplant TL has been measured in controls, donors, and HSCT recipients in collaboration with the National Marrow Donor Program (NMDP) and the Center for International Blood and Marrow transplant research (CIBMTR). Ongoing analyses include the association of TL with HSCT outcomes such as death, post-transplant malignancies, and fibrotic diseases. Population genetic studies of telomere biology genes [CAS 10372] continue to provide important insight into their evolutionary history. This will improve understanding of the role of genetic variation in their function and aid in understanding these variants as cancer risk factors. We expanded on our initial study of seven genes by evaluating 37 telomere biology genes in 53 worldwide populations utilizing SNP data from the Human Genome Diversity Panel. This study showed that, as a group, telomere biology genes have low to moderate haplotype diversity, high ancestral allele frequencies, and low differentiation. The telomerase gene (TERT) was a notable exception with low levels of linkage disequilibrium. Evidence suggestive of evolutionary selection was present in five genes. Ongoing studies include detailed studies of genetic variation in the 5p15.33 chromosomal locus using 1000 Genomes data. This locus includes TERT and CLPTM1L and includes SNPs which have been associated with cancer risk in several GWAS.

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Burris, Ashley M; Ballew, Bari J; Kentosh, Joshua B et al. (2016) Hoyeraal-Hreidarsson Syndrome due to PARN Mutations: Fourteen Years of Follow-Up. Pediatr Neurol 56:62-68.e1
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Savage, Sharon A; Pulsipher, Michael A; Romano, Alessandra et al. (2013) Aplastic Anemia & MDS International Foundation (AA&MDSIF): bone marrow failure disease scientific symposium 2012. Leuk Res 37:848-51

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