@article {Artomov162479, author = {Mykyta Artomov and Joseph Vijai and Grace Tiao and Tinu Thomas and Kasmintan Schrader and Robert Klein and Adam Kiezun and Namrata Gupta and Lauren Margolin and Alexander J. Stratigos and Ivana Kim and Kristen Shannon and Leif W. Ellisen and Daniel Haber and Gad Getz and Hensin Tsao and Steven Lipkin and David Altshuler and Kenneth Offit and Mark J. Daly}, title = {A Strategy for Large-Scale Systematic Pan-Cancer Germline Rare Variation Analysis}, elocation-id = {162479}, year = {2017}, doi = {10.1101/162479}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Traditionally, genetic studies in cancer are focused on somatic mutations found in tumors and absent from the normal tissue. However, this approach omits inherited component of the cancer risk. We assembled exome sequences from about 2,000 patients with different types of cancers: breast cancer, colon cancer and cutaneous and ocular melanomas matched to more than 7,000 non-cancer controls. Using this dataset, we described germline variation in the known cancer genes grouped by inheritance mode or inclusion in a known cancer pathway. According to our observations, protein-truncating singleton variants in loss-of-function tolerant genes following autosomal dominant inheritance mode are driving the association signal in both genetically enriched and unselected cancer cases. We also performed separate gene-based association analysis for individual phenotypes and proposed a list of new cancer risk gene candidates. Taken together, these results extend existing knowledge of germline variation contribution to cancer onset and provide a strategy for novel gene discovery.}, URL = {https://www.biorxiv.org/content/early/2017/07/12/162479}, eprint = {https://www.biorxiv.org/content/early/2017/07/12/162479.full.pdf}, journal = {bioRxiv} }