Interaction landscape of inherited polymorphisms with somatic events in cancer

Hannah Carter*, Rachel Marty, Matan Hofree, Andrew M. Gross, James Jensen, Kathleen M. Fisch, Xingyu Wu, Christopher Deboever, Eric L. Van Nostrand, Yan Song, Emily Wheeler, Jason F. Kreisberg, Scott M. Lippman, Gene W. Yeo, J. Silvio Gutkind, Trey Ideker

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

106 Scopus citations

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.

Original languageAmerican English
Pages (from-to)410-423
Number of pages14
JournalCancer Discovery
Volume7
Issue number4
DOIs
StatePublished - Apr 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 American Association for Cancer Research.

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