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Nat Commun. 2015 Dec 22;6:10086. doi: 10.1038/ncomms10086.

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

Author information

1
The McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
2
Department of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
3
Department of Genetics, Washington University in St. Louis, St Louis, Missouri 63108, USA.
4
Department of Mathematics, Washington University in St. Louis, St Louis, Missouri 63108, USA.
5
Department of Computer Science, Brown University, Providence, Rhode Island 02912, USA.
6
Center for Computational Molecular Biology, Brown University, Providence, Rhode Island 02912, USA.
7
The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
8
Siteman Cancer Center, Washington University in St Louis, St Louis, Missouri 63108, USA.
9
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
10
Brown School Master of Public Health Program, Washington University in St Louis, St Louis, Missouri 63130, USA.
11
Department of Biomedical Informatics and, Ohio State University, Columbus, Ohio 43210, USA.

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.

PMID:
26689913
PMCID:
PMC4703835
DOI:
10.1038/ncomms10086
[Indexed for MEDLINE]
Free PMC Article

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