Journal Article

Patterns and functional implications of rare germline variants across 12 cancer types

Mardis, Elaine R., Parvin, Jeffrey D., Lu, Charles, Tripathi, Piyush, Miller, Christopher A., Wang, Jiayin, Kanchi, Krishna L., You, Ming, Wyczalkowski, Matthew A., Ye, Kai, Welch, John S., Walter, Matthew J., Govindan, Ramaswamy, McLellan, Michael D., Koboldt, Daniel C., Larson, David E., Leiserson, Mark D. M., Ding, Li, McMichael, Joshua F., Graubert, Timothy A., Dipersio, John F., Wendl, Michael C., Huang, Kuan-lin, Wilson, Richard K., Banerjee, Tapahsama, Eldred, James M., Ozenberger, Bradley A., Johnson, Kimberly J., Batra, Prag, Zhang, Qunyuan, Jayasinghe, Reyka, Ellis, Matthew J., Kandoth, Cyriac, Xie, Mingchao, Ley, Timothy J., Raphael, Benjamin J., Chen, Feng, Schmidt, Heather K., Fulton, Robert S., Bharadwaj, Maheetha, Goodfellow, Paul J., Ning, Jie, Niu, Beifang

2015

Overview

Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C , PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes ( ATM , BAP1 , BRCA1/2 , BRIP1 , FANCM , PALB2 and RAD51C/D ). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine. Published sequencing data sets of cancer samples could be used to identify genetic variants associated with the risk of developing cancer. Here, Lu et al . analyse over 4,000 tumour-normal pairs to reveal variable frequencies of inherited susceptibilities across 12 cancer types and find enrichment of functionally validated missense variants of unknown significance.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/726/649 / 631/67/68 / Adolescent / Adult / Aged / Aged, 80 and over / Breast cancer / Child / Female / Genetic Predisposition to Disease / Genetic Variation / Humanities and Social Sciences / Humans / Leukemia / Male / Middle Aged / multidisciplinary / Mutation / Neoplasms - classification / Neoplasms - epidemiology / Neoplasms - genetics / Neoplasms - metabolism / Ovarian cancer / Science / Science (multidisciplinary) / United States - epidemiology / Young Adult