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Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun 2015 Dec 22;6:10086 PMID: 26689913 PMCID: PMC4703835

Pubmed ID

26689913

DOI

10.1038/ncomms10086

Abstract

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.

Author List

Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, Huang KL, Wyczalkowski MA, Jayasinghe R, Banerjee T, Ning J, Tripathi P, Zhang Q, Niu B, Ye K, Schmidt HK, Fulton RS, McMichael JF, Batra P, Kandoth C, Bharadwaj M, Koboldt DC, Miller CA, Kanchi KL, Eldred JM, Larson DE, Welch JS, You M, Ozenberger BA, Govindan R, Walter MJ, Ellis MJ, Mardis ER, Graubert TA, Dipersio JF, Ley TJ, Wilson RK, Goodfellow PJ, Raphael BJ, Chen F, Johnson KJ, Parvin JD, Ding L

Author

Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




Scopus

2-s2.0-84951293785   78 Citations

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Aged
Aged, 80 and over
Child
Female
Genetic Predisposition to Disease
Genetic Variation
Humans
Male
Middle Aged
Mutation
Neoplasms
United States
Young Adult
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e