Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival.
Syed H ZaidiTabitha A HarrisonAmanda I PhippsRobert SteinfelderQuang M TrinhConghui QuBarbara L BanburyPeter GeorgesonCatherine S GrassoMarios GiannakisJeremy B AdamsElizabeth AlwersEfrat L AmitayRichard T BarfieldSonja I BerndtIvan BorozanHermann BrennerStefanie BrezinaDaniel D BuchananYin CaoAndrew T ChanJenny Chang-ClaudeCharles M ConnollyDavid A DrewAlton Brad FarrisJane C FigueiredoAmy J FrenchCharles S FuchsLevi A GarrawaySteve GruberMark A GuinterStanley R HamiltonSophia HarlidLawrence E HeislerAkihisa HidakaJohn L HopperWen-Yi HuangJeroen R HuygheMark E JenkinsPaul M KrzyzanowskiMathieu LemireYi LinXuemei LuoElaine R MardisJohn D McPhersonJessica K MillerVictor MorenoXinmeng Jasmine MuReiko NishiharaNickolas PapadopoulosDanielle PasternackMichael J QuistAdilya RafikovaEmma E G ReidEve ShinbrotBrian H ShirtsLincoln D SteinCherie D TeneyLee TimmsCaroline Y UmBethany Van GuelpenMegan Van TasselXiaolong WangDavid A WheelerChristina K YungLi HsuShuji OginoAndrea GsurPolly A NewcombSteven GallingerMichael HoffmeisterPeter T CampbellStephen N ThibodeauWei SunThomas J HudsonUlrike PetersPublished in: Nature communications (2020)
Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.