A Strategy for Large-Scale Systematic Pan-Cancer Germline Rare Variation Analysis
A Strategy for Large-Scale Systematic Pan-Cancer Germline Rare Variation Analysis
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.
Vijai Joseph、Tiao Grace、Schrader Kasmintan、Kiezun Adam、Ellisen Leif W.、Haber Daniel、Getz Gad、Lipkin Steven、Altshuler David、Shannon Kristen、Offit Kenneth、Tsao Hensin、Thomas Tinu、Artomov Mykyta、Kim Ivana、Daly Mark J.、Gupta Namrata、Klein Robert、Margolin Lauren、Stratigos Alexander J.
Clinical Genetics Research Laboratory, Department of Medicine, Memorial Sloan Kettering Cancer CenterBroad Institute, CambridgeClinical Genetics Research Laboratory, Department of Medicine, Memorial Sloan Kettering Cancer CenterBroad Institute, CambridgeMassachusetts General Hospital Cancer Center||Harvard Medical SchoolMassachusetts General Hospital Cancer Center||Harvard Medical School||Howard Hughes Medical InstituteBroad Institute, CambridgeDepartment of Medicine, Weill-Cornell MedicineBroad Institute, CambridgeMassachusetts General Hospital Cancer CenterClinical Genetics Research Laboratory, Department of Medicine, Memorial Sloan Kettering Cancer Center||Cancer Biology and Genetics Program, Sloan Kettering InstituteDepartment of Dermatology, Wellman Center for Photomedicine||Melanoma Genetics Program, MGH Cancer CenterClinical Genetics Research Laboratory, Department of Medicine, Memorial Sloan Kettering Cancer CenterAnalytic and Translational Genetics Unit||Broad Institute, Cambridge||Department of Chemistry and Chemical Biology, Harvard University, CambridgeRetina Service, Massachusetts Eye and Ear InfirmaryAnalytic and Translational Genetics Unit||Broad Institute, CambridgeBroad Institute, CambridgeClinical Genetics Research Laboratory, Department of Medicine, Memorial Sloan Kettering Cancer CenterBroad Institute, Cambridge1st Department of Dermatology-Venereology, National and Kapodistrian Universityof Athens School of Medicine
肿瘤学遗传学生物科学研究方法、生物科学研究技术
Vijai Joseph,Tiao Grace,Schrader Kasmintan,Kiezun Adam,Ellisen Leif W.,Haber Daniel,Getz Gad,Lipkin Steven,Altshuler David,Shannon Kristen,Offit Kenneth,Tsao Hensin,Thomas Tinu,Artomov Mykyta,Kim Ivana,Daly Mark J.,Gupta Namrata,Klein Robert,Margolin Lauren,Stratigos Alexander J..A Strategy for Large-Scale Systematic Pan-Cancer Germline Rare Variation Analysis[EB/OL].(2025-03-28)[2025-04-30].https://www.biorxiv.org/content/10.1101/162479.点此复制
评论