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 a genome-wide association study. In the American and Italian melanoma-prone families, we are using novel technologies including array comparative genomic hybridization (aCGH) and next generation sequencing to search for new high-risk melanoma susceptibility genes. We continue to accrue and evaluate new families in both the U.S and Italy. We have continued to evaluate families of individuals with heritable retinoblastoma and melanoma. The study of familial chordoma, a rare, low-grade, malignant bone tumor derived from remnants of the notochord, was expanded to include additional families. Recently we used array CGH to determine that duplications of the T gene (brachyury), which is important in notocord development, and is expressed in most sporadic chordomas, co-segregated with chordoma in members of four multiplex chordoma families. This was the first example of gene duplication conferring major familial susceptibility to cancer. We are currently using exome sequencing to search for disease-causing mutations in chordoma families without T gene duplications. 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 conducted immunophenotypic and expression studies in 101 MBL cases from high risk CLL families. In all, 91 unique MBL clones were detected: 73 CLL-like MBL (CD5(+)CD20(dim)sIg(dim)), 11 atypical MBL (CD5(+)CD20(+)sIg(+)) and 7 CD5(neg) MBL (CD5(neg)CD20(+)sIg(neg)). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70 and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on seven CLL-like MBL, and showed activation of B-cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders. We performed a GWAS study in 407 CLL cases (of which 102 had a family history of CLL) and 296 controls and also looked specifically at the familial cases. Our top hits from these analyses were evaluated in an additional sample of 252 familial CLL cases and 965 controls. Using all available data, we identified and confirmed an independent association of 4 single-nucleotide polymorphisms (SNPs) that met genome-wide statistical significance within the IRF8 (interferon regulatory factor 8) gene (combined P values 3.37 10(-8)), located in the previously identified 16q24.1 locus. Subsetting to familial CLL cases, we identified and confirmed a new locus on chromosome 6p21.3 (combined P value = 6.92 10(-9)). This novel region harbors the HLA-DQA1 and HLA-DRB5 genes. Our findings support the hypothesis that familial CLL cases have additional genetic variants not seen in sporadic CLL.We also continued a family study of Xeroderma pigmentosum in collaboration with CCR investigators to assess risk of cancer in XP heterozygotes. Data collection is underway. Neurologic degeneration is a major cause of morbidity and mortality among XP patients, and varies by subgroup. We have also documented that mothers carrying affected children with tricothiodystrophy have more pregnancy complications than when carrying unaffected children.

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National Cancer Institute (NCI)
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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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