title: Interaction Landscape of Inherited Polymorphisms with Somatic Events in Cancer.
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 inRBFOX1that increased incidence ofSF3B1somatic 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 inPTEN.In support of this association, we found thatPTENknockdown sensitizes theMTORpathway to high expression of the 19p13.3 geneGNA11Finally, 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.
authors.affiliation: Department of Medicine, Division of Medical Genetics, University of California, San Diego, La Jolla, California. hkcarter@ucsd.edu.|Moores Cancer Center, University of California, San Diego, La Jolla, California.|Cancer Cell Map Initiative (CCMI), La Jolla and San Francisco, California.|Institute for Genomic Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Hannah
authors.initials: H
authors.lastname: Carter
authors.affiliation: Bioinformatics Program, University of California, San Diego, La Jolla, California.
authors.forename: Rachel
authors.initials: R
authors.lastname: Marty
authors.affiliation: Department of Computer Science, University of California, San Diego, La Jolla, California.
authors.forename: Matan
authors.initials: M
authors.lastname: Hofree
authors.affiliation: Bioinformatics Program, University of California, San Diego, La Jolla, California.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Gross
authors.affiliation: Bioinformatics Program, University of California, San Diego, La Jolla, California.
authors.forename: James
authors.initials: J
authors.lastname: Jensen
authors.affiliation: Department of Medicine, Division of Medical Genetics, University of California, San Diego, La Jolla, California.|Moores Cancer Center, University of California, San Diego, La Jolla, California.|Cancer Cell Map Initiative (CCMI), La Jolla and San Francisco, California.|Department of Medicine, Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, California.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Fisch
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Wu
authors.affiliation: Bioinformatics Program, University of California, San Diego, La Jolla, California.
authors.forename: Christopher
authors.initials: C
authors.lastname: DeBoever
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, California.|Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Van Nostrand
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, California.|Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Yan
authors.initials: Y
authors.lastname: Song
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, California.|Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Emily
authors.initials: E
authors.lastname: Wheeler
authors.affiliation: Department of Medicine, Division of Medical Genetics, University of California, San Diego, La Jolla, California.|Cancer Cell Map Initiative (CCMI), La Jolla and San Francisco, California.
authors.forename: Jason F
authors.initials: JF
authors.lastname: Kreisberg
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.affiliation: Institute for Genomic Medicine, University of California, San Diego, La Jolla, California.|Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California.|Cancer Cell Map Initiative (CCMI), La Jolla and San Francisco, California.
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.affiliation: Department of Medicine, Division of Medical Genetics, University of California, San Diego, La Jolla, California.|Moores Cancer Center, University of California, San Diego, La Jolla, California.|Cancer Cell Map Initiative (CCMI), La Jolla and San Francisco, California.|Institute for Genomic Medicine, University of California, San Diego, La Jolla, California.|Bioinformatics Program, University of California, San Diego, La Jolla, California.|Department of Computer Science, University of California, San Diego, La Jolla, California.
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker
mesh_terms: D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D023281:Genomics; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D011110:Polymorphism, Genetic; D012326:RNA Splicing / Q000235:genetics; D000072260:RNA Splicing Factors / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics
chemical_list: C554062:GNA11 protein, human; D044385:GTP-Binding Protein alpha Subunits; D010750:Phosphoproteins; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; C112491:SF3B1 protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human