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ARTICLEdoi:10.1038/nature10983Thegenomicandtranscriptomicarchitectureof2,000breasttumoursrevealsnovelsubgroupsChristinaCurtis1,2{*,SohrabP.Shah3,4*,Suet-FeungChin1,2*,GulisaTurashvili3,4*,OscarM.Rueda1,2,MarkJ.Dunning2,DougSpeed2,5{,AndyG.Lynch1,2,ShamithSamarajiwa1,2,YinyinYuan1,2,StefanGra¨f1,2,GavinHa3,GholamrezaHaffari3,AliBashashati3,RoslinRussell2,StevenMcKinney3,4,METABRICGroup{,AnitaLangerød6,AndrewGreen7,ElenaProvenzano8,GordonWishart8,SarahPinder9,PeterWatson3,4,10,FlorianMarkowetz1,2,LeighMurphy10,IanEllis7,ArniePurushotham9,11,Anne-LiseBørresen-Dale6,12,JamesD.Brenton2,13,SimonTavare´1,2,5,14,CarlosCaldas1,2,8,13&SamuelAparicio3,4Theelucidationofbreastcancersubgroupsandtheirmoleculardriversrequiresintegratedviewsofthegenomeandtranscriptomefromrepresentativenumbersofpatients.Wepresentanintegratedanalysisofcopynumberandgeneexpressioninadiscoveryandvalidationsetof997and995primarybreasttumours,respectively,withlong-termclinicalfollow-up.Inheritedvariants(copynumbervariantsandsinglenucleotidepolymorphisms)andacquiredsomaticcopynumberaberrations(CNAs)wereassociatedwithexpressionin40%ofgenes,withthelandscapedominatedbycis-andtrans-actingCNAs.BydelineatingexpressionoutliergenesdrivenincisbyCNAs,weidentifiedputativecancergenes,includingdeletionsinPPP2R2A,MTAPandMAP2K4.UnsupervisedanalysisofpairedDNA–RNAprofilesrevealednovelsubgroupswithdistinctclinicaloutcomes,whichreproducedinthevalidationcohort.Theseincludeahigh-risk,oestrogen-receptor-positive11q13/14cis-actingsubgroupandafavourableprognosissubgroupdevoidofCNAs.Trans-actingaberrationhotspotswerefoundtomodulatesubgroup-specificgenenetworks,includingaTCRdeletion-mediatedadaptiveimmuneresponseinthe‘CNA-devoid’subgroupandabasal-specificchromosome5deletion-associatedmitoticnetwork.Ourresultsprovideanovelmolecularstratificationofthebreastcancerpopulation,derivedfromtheimpactofsomaticCNAsonthetranscriptome.Inheritedgeneticvariationandacquiredgenomicaberrationscontrib-utetobreastcancerinitiationandprogression.AlthoughsomaticallyacquiredCNAsarethedominantfeatureofsporadicbreastcancers,thedrivereventsthatareselectedforduringtumorigenesisaredifficulttoelucidateastheyco-occuralongsideamuchlargerlandscapeofrandomnon-pathogenicpassengeralterations1,2andgermlinecopynumbervariants(CNVs).Attemptstodefinesubtypesofbreastcancerandtodiscernpossiblesomaticdriversarestillintheirrelativeinfancy3–6,inpartbecausebreastcancerrepresentsmultiplediseases,implyingthatlargenumbers(manyhundredsorthousands)ofpatientsmustbestudied.Herewedescribeanintegratedgenomic/transcriptomicanalysisofbreastcancerswithlong-termclinicaloutcomescomposedofadiscoverysetof997primarytumoursandavalidationsetof995tumoursfromMETABRIC(MolecularTaxonomyofBreastCancerInternationalConsortium).AbreastcancerpopulationgenomicresourceWeassembledacollectionofover2,000clinicallyannotatedprimaryfresh-frozenbreastcancerspecimensfromtumourbanksintheUKandCanada(SupplementaryTables1–3).Nearlyalloestrogenreceptor(ER)-positiveand/orlymphnode(LN)-negativepatientsdidnotreceivechemotherapy,whereasER-negativeandLN-positivepatientsdid.Additionally,noneoftheHER21patientsreceivedtrastuzumab.Assuch,thetreatmentswerehomogeneouswithrespecttoclinicallyrelevantgroupings.Aninitialsetof997tumourswasanalysedasadiscoverygroupandafurthersetof995tumours,forwhichcompletedatalaterbecameavailable,wasusedtotestthereproducibilityoftheintegrativeclusters(describedbelow).AnoverviewofthemainanalyticalapproachesisprovidedinSupplementaryFig.1.Detailsconcerningexpressionandcopynumberprofiling,includingsampleassignmenttothePAM50intrinsicsubtypes3,4,7(SupplementaryFig.2),copynumberanalysis(SupplementaryTables4–8)andvalidation(SupplementaryFigs3and4andSupplementaryTables9–11),andTP53mutationalprofiling(SupplementaryFig.5)aredescribedintheSupplementaryInformation.GenomevariationaffectstumourexpressionarchitectureGenomicvariantsareconsideredtoactinciswhenavariantatalocushasanimpactonitsownexpression,orintranswhenitisassociated*Theseauthorscontributedequallytothiswork.{Listsofparticipantsandaffiliationsappearattheendofthepaper.1DepartmentofOncology,UniversityofCambridge,HillsRoad,CambridgeCB22XZ,UK.2CancerResearchUK,CambridgeResearchInstitute,LiKaShingCentre,RobinsonWay,CambridgeCB20RE,UK.3DepartmentofPathologyandLaboratoryMedicine,UniversityofBritishColumbia,Vancouver,BritishColumbiaV6T2B5,Canada.4MolecularOncology,BritishColumbiaCancerResearchCentre,Vancouver,BritishColumbiaV5Z1L3,Canada.5DepartmentofAppliedMathematicsandTheoreticalPhysics,UniversityofCambridge,CentreforMathematicalSciences,CambridgeCB30WA,UK.6DepartmentofGenetics,InstituteforCancerResearch,OsloUniversityHospitalRadiumhospitalet,Montebello,0310Oslo,Norway.7DepartmentofHistopathology,SchoolofMolecularMedicalSciences,UniversityofNottingham,NottinghamNG51PB,UK.8CambridgeBreastUnit,Addenbrooke’sHospital,CambridgeUniversityHospitalNHSFoundationTrustandNIHRCambridgeBiomedicalResearchCentre,CambridgeCB22QQ,UK.9King’sCollegeLondon,BreakthroughBreastCancerResearchUnit,LondonWC2R2LS,UK.10ManitobaIns