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Cancer Discov. 2017 Apr;7(4):410-423. doi: 10.1158/2159-8290.CD-16-1045. Epub 2017 Feb 10.

Interaction Landscape of Inherited Polymorphisms with Somatic Events in Cancer.

Author information

1
Department of Medicine, Division of Medical Genetics, University of California, San Diego, La Jolla, California. hkcarter@ucsd.edu.
2
Moores Cancer Center, University of California, San Diego, La Jolla, California.
3
Cancer Cell Map Initiative (CCMI), La Jolla and San Francisco, California.
4
Institute for Genomic Medicine, University of California, San Diego, La Jolla, California.
5
Bioinformatics Program, University of California, San Diego, La Jolla, California.
6
Department of Computer Science, University of California, San Diego, La Jolla, California.
7
Department of Medicine, Division of Medical Genetics, University of California, San Diego, La Jolla, California.
8
Department of Medicine, Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, California.
9
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California.

Abstract

Recent studies have characterized the extensive somatic alterations that arise during cancer. However, the somatic evolution of a tumor may be significantly affected by inherited polymorphisms carried in the germline. Here, we analyze genomic data for 5,954 tumors to reveal and systematically validate 412 genetic interactions between germline polymorphisms and major somatic events, including tumor formation in specific tissues and alteration of specific cancer genes. Among germline-somatic interactions, we found germline variants in RBFOX1 that increased incidence of SF3B1 somatic mutation by 8-fold via functional alterations in RNA splicing. Similarly, 19p13.3 variants were associated with a 4-fold increased likelihood of somatic mutations in PTEN. In support of this association, we found that PTEN knockdown sensitizes the MTOR pathway to high expression of the 19p13.3 gene GNA11 Finally, we observed that stratifying patients by germline polymorphisms exposed distinct somatic mutation landscapes, implicating new cancer genes. This study creates a validated resource of inherited variants that govern where and how cancer develops, opening avenues for prevention research.Significance: This study systematically identifies germline variants that directly affect tumor evolution, either by dramatically increasing alteration frequency of specific cancer genes or by influencing the site where a tumor develops. Cancer Discovery; 7(4); 410-23. ©2017 AACR.See related commentary by Geeleher and Huang, p. 354This article is highlighted in the In This Issue feature, p. 339.

PMID:
28188128
PMCID:
PMC5460679
DOI:
10.1158/2159-8290.CD-16-1045
[Indexed for MEDLINE]
Free PMC Article

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