title: Diverse somatic mutation patterns and pathway alterations in human cancers.
abstract: The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics. Here we report the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumours comprising breast, lung, ovarian and prostate cancer types and subtypes. We found that mutation rates and the sets of mutated genes varied substantially across tumour types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G-protein-coupled receptors such as GRM8, BAI3, AGTRL1 (also called APLNR) and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS, indicating an expanded role for galpha subunits in multiple cancer types. Furthermore, our experimental analyses demonstrate the functional roles of mutant GNAO1 (a Galpha subunit) and mutant MAP2K4 (a member of the JNK signalling pathway) in oncogenesis. Our study provides an overview of the mutational spectra across major human cancers and identifies several potential therapeutic targets.
authors.affiliation: Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Zhengyan
authors.initials: Z
authors.lastname: Kan
authors.forename: Bijay S
authors.initials: BS
authors.lastname: Jaiswal
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.forename: Vasantharajan
authors.initials: V
authors.lastname: Janakiraman
authors.forename: Deepali
authors.initials: D
authors.lastname: Bhatt
authors.forename: Howard M
authors.initials: HM
authors.lastname: Stern
authors.forename: Peng
authors.initials: P
authors.lastname: Yue
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haverty
authors.forename: Richard
authors.initials: R
authors.lastname: Bourgon
authors.forename: Jianbiao
authors.initials: J
authors.lastname: Zheng
authors.forename: Martin
authors.initials: M
authors.lastname: Moorhead
authors.forename: Subhra
authors.initials: S
authors.lastname: Chaudhuri
authors.forename: Lynn P
authors.initials: LP
authors.lastname: Tomsho
authors.forename: Brock A
authors.initials: BA
authors.lastname: Peters
authors.forename: Kanan
authors.initials: K
authors.lastname: Pujara
authors.forename: Shaun
authors.initials: S
authors.lastname: Cordes
authors.forename: David P
authors.initials: DP
authors.lastname: Davis
authors.forename: Victoria E H
authors.initials: VE
authors.lastname: Carlton
authors.forename: Wenlin
authors.initials: W
authors.lastname: Yuan
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Kaminker
authors.forename: David A
authors.initials: DA
authors.lastname: Eberhard
authors.forename: Paul
authors.initials: P
authors.lastname: Waring
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Schuster
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Zemin
authors.initials: Z
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Stokoe
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.forename: Malek
authors.initials: M
authors.lastname: Faham
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
mesh_terms: D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000145:classification / Q000235:genetics; D048670:MAP Kinase Kinase 4 / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000145:classification / Q000235:genetics; D011471:Prostatic Neoplasms / Q000145:classification / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D043562:Receptors, G-Protein-Coupled; D011494:Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human