Diverse somatic mutation patterns and pathway alterations in human cancers
Zhengyan Kan,Bijay S. Jaiswal,Jeremy Stinson,Vasantharajan Janakiraman,Deepali Bhatt,Howard M. Stern,Peng Yue,Peter M. Haverty,Richard Bourgon,Jianbiao Zheng,Martin Moorhead,Subhra Chaudhuri,Lynn P. Tomsho,Brock A. Peters,Kanan Pujara,Shaun Cordes,David P. Davis,Victoria E. H. Carlton,Wenlin Yuan,Li Li,Weiru Wang,Charles Eigenbrot,Joshua S. Kaminker,David A. Eberhard,Paul Waring,Stephan C. Schuster,Zora Modrusan,Zemin Zhang,David Stokoe,Frederic J. de Sauvage, Malek Faham & Somasekar Seshagiri et al.
The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics1. Here we report the identification of 2,576 somatic mutations across ~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 gα subunits in multiple cancer types. Furthermore, our experimental analyses demonstrate the functional roles of mutant GNAO1 (a Gα 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.