Most Genetic Epidemiology Branch investigations evaluate the contributions of host susceptibility and environmental exposure in the development of cancer. In family studies, the host susceptibility measure is frequently an alteration in specific gene(s). These studies tend to be very long term with varying activity. Although two genes associated with melanoma susceptibility have been identified (CDKN2A and CDK4), alterations in these genes are found in only a small percentage of melanoma-prone families. The search for other genes continues; in collaboration with an international consortium (GenoMEL), a search for new melanoma susceptibility genes continues both within families and genome-wide association studies. In the American and Italian melanoma-prone families, we are using novel technologies including array comparative genomic hybridization (aCGH) and next generation sequencing (exomic and whole genome) to search for new high-risk melanoma susceptibility genes. In the past year, we have found another high-risk susceptibility gene, POT-1 in Italian and American families. We continue to accrue and evaluate new families in both the U.S., Italy, and Spain. We have continued to evaluate families of individuals with heritable retinoblastoma and melanoma. We are conducting exome sequencing in retinoblastoma survivors who have developed second malignancies. The study of familial chordoma, a rare, low-grade, malignant bone tumor derived from remnants of the notochord, was expanded to include additional families. Although we have reported duplications of the T gene (brachyury) as a major genetic risk factor for familial chordoma, several families do not have abnormalities in the T gene. We are conducting next generation exomic sequencing in the families without identified high risk susceptibility genes. Studying families with lymphoproliferative cancers has been a long-standing interest. We have collaborated with the Genetic Epidemiology of CLL Consortium to conduct larger studies of familial CLL. We are using exomic and whole genome sequencing to search for high risk susceptibility genes in CLL , HD, WM, and NHL families. We also continued a family study of Xeroderma pigmentosum in collaboration with CCR investigators to assess risk of cancer in XP heterozygotes. Data collection continues.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIACP004410-42
Application #
9770237
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
42
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cancer Epidemiology and Genetics
Department
Type
DUNS #
City
State
Country
Zip Code
Zhou, Weiyin; Goldin, Lynn; Wang, Mingyi et al. (2018) Combined somatic mutation and copy number analysis in the survival of familial CLL. Br J Haematol 181:604-613
Goldstein, Alisa M; Xiao, Yanzi; Sampson, Joshua et al. (2017) Rare germline variants in known melanoma susceptibility genes in familial melanoma. Hum Mol Genet 26:4886-4895
Helgadottir, Hildur; Olsson, Håkan; Tucker, Margaret A et al. (2017) Phenocopies in melanoma-prone families with germ-line CDKN2A mutations. Genet Med :
Baker, Maria J; Goldstein, Alisa M; Gordon, Patricia L et al. (2016) An interstitial deletion within 9p21.3 and extending beyond CDKN2A predisposes to melanoma, neural system tumours and possible haematological malignancies. J Med Genet :
Shi, Jianxin; Zhou, Weiyin; Zhu, Bin et al. (2016) Rare Germline Copy Number Variations and Disease Susceptibility in Familial Melanoma. J Invest Dermatol 136:2436-2443
Castillo, Jorge J; Garcia-Sanz, Ramon; Hatjiharissi, Evdoxia et al. (2016) Recommendations for the diagnosis and initial evaluation of patients with Waldenström Macroglobulinaemia: A Task Force from the 8th International Workshop on Waldenström Macroglobulinaemia. Br J Haematol 175:77-86
Goldin, Lynn R; McMaster, Mary L; Rotunno, Melissa et al. (2016) Whole exome sequencing in families with CLL detects a variant in Integrin ? 2 associated with disease susceptibility. Blood 128:2261-2263
Yang, Xiaohong R; Rotunno, Melissa; Xiao, Yanzi et al. (2016) Multiple rare variants in high-risk pancreatic cancer-related genes may increase risk for pancreatic cancer in a subset of patients with and without germline CDKN2A mutations. Hum Genet 135:1241-1249
Rotunno, Melissa; Sun, Xuezheng; Figueroa, Jonine et al. (2014) Parity-related molecular signatures and breast cancer subtypes by estrogen receptor status. Breast Cancer Res 16:R74
Shi, Jianxin; Yang, Xiaohong R; Ballew, Bari et al. (2014) Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet 46:482-6

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