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 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 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 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.