Diverse somatic mutation patterns and pathway alterations in human cancers.
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.
Kan
Zhengyan
Z
Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Jaiswal
Bijay S
BS
Stinson
Jeremy
J
Janakiraman
Vasantharajan
V
Bhatt
Deepali
D
Stern
Howard M
HM
Yue
Peng
P
Haverty
Peter M
PM
Bourgon
Richard
R
Zheng
Jianbiao
J
Moorhead
Martin
M
Chaudhuri
Subhra
S
Tomsho
Lynn P
LP
Peters
Brock A
BA
Pujara
Kanan
K
Cordes
Shaun
S
Davis
David P
DP
Carlton
Victoria E H
VE
Yuan
Wenlin
W
Li
Li
L
Wang
Weiru
W
Eigenbrot
Charles
C
Kaminker
Joshua S
JS
Eberhard
David A
DA
Waring
Paul
P
Schuster
Stephan C
SC
Modrusan
Zora
Z
Zhang
Zemin
Z
Stokoe
David
D
de Sauvage
Frederic J
FJ
Faham
Malek
M
Seshagiri
Somasekar
S
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*
D044385:GTP-Binding Protein alpha Subunits; D043562:Receptors, G-Protein-Coupled; D011494:Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human