Next-generation characterization of the Cancer Cell Line ...

Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a ... Skiptomaincontent Thankyouforvisitingnature.com.YouareusingabrowserversionwithlimitedsupportforCSS.Toobtain thebestexperience,werecommendyouuseamoreuptodatebrowser(orturnoffcompatibilitymodein InternetExplorer).Inthemeantime,toensurecontinuedsupport,wearedisplayingthesitewithoutstyles andJavaScript. Advertisement nature articles article Subjects CancergenomicsCancermodels AbstractLargepanelsofcomprehensivelycharacterizedhumancancermodels,includingtheCancerCellLineEncyclopedia(CCLE),haveprovidedarigorousframeworkwithwhichtostudygeneticvariants,candidatetargets,andsmall-moleculeandbiologicaltherapeuticsandtoidentifynewmarker-drivencancerdependencies.Toimproveourunderstandingofthemolecularfeaturesthatcontributetocancerphenotypes,includingdrugresponses,herewehaveexpandedthecharacterizationsofcancercelllinestoincludegenetic,RNAsplicing,DNAmethylation,histoneH3modification,microRNAexpressionandreverse-phaseproteinarraydatafor1,072celllinesfromindividualsofvariouslineagesandethnicities.Integrationofthesedatawithfunctionalcharacterizationssuchasdrug-sensitivity,shorthairpinRNAknockdownandCRISPR–Cas9knockoutdatarevealspotentialtargetsforcancerdrugsandassociatedbiomarkers.Together,thisdatasetandanaccompanyingpublicdataportalprovidearesourcefortheaccelerationofcancerresearchusingmodelcancercelllines. Yourinstitutedoesnothaveaccesstothisarticle Relevantarticles OpenAccessarticlescitingthisarticle. Widespreadredundancyin-omicsprofilesofcancermutationstates JakeCrawford,BrockC.Christensen … CaseyS.Greene GenomeBiology OpenAccess 27June2022 3Dgenomeorganizationintheepithelial-mesenchymaltransitionspectrum QingYouPang,TuanZeaTan … RubyYun-JuHuang GenomeBiology OpenAccess 30May2022 classifieRaflexibleinteractivecloud-applicationforfunctionalannotationofcancertranscriptomes GerardP.Quinn,TamasSessler … SimonS.McDade BMCBioinformatics OpenAccess 31March2022 Accessoptions Accessthroughyourinstitution Changeinstitution Buyorsubscribe SubscribetoJournalGetfulljournalaccessfor1year185,98€only3,65€perissueSubscribeAllpricesareNETprices.VATwillbeaddedlaterinthecheckout.Taxcalculationwillbefinalisedduringcheckout.BuyarticleGettimelimitedorfullarticleaccessonReadCube.$32.00BuyAllpricesareNETprices. Additionalaccessoptions: Login Learnaboutinstitutionalsubscriptions Fig.1:Overviewofthedatasets.Fig.2:DNAmethylationandcancerdependence.Fig.3:Globalchromatinprofilingrevealsactivatingmutationsinp300andCBP.Fig.4:MDM4exon6inclusionisassociatedwithMDM4dependencyandRPL22orRPL22L1status.Fig.5:HighpSHP2isamarkerofSHP2dependenceandsensitivitytoRTKinhibitors. Dataavailability AlltheCCLEprocesseddatasetsareavailableattheCCLEportal(www.broadinstitute.org/ccle)andDepMapportal(http://www.depmap.org).RawsequencingdataareavailableatSequenceReadArchive(SRA)underaccessionnumberPRJNA523380.AchillesRNAidata(DEMETERscores)weredownloadedfromhttps://portals.broadinstitute.org/achilles.TheProject AchillesCRISPRAvana18Q3publicdataset(geneeffects,CERESscores)wasdownloadedfromhttps://figshare.com/articles/DepMap_Achilles_18Q3_public/6931364/1.NovartisProjectDRIVERNAidataset(ATARiSscores)wasobtainedfromtheProjectDRIVEauthors.CTRPAUCscoreswasdownloadedfromtheNCIwebsite(ftp://caftpd.nci.nih.gov/pub/OCG-DCC/CTD2/Broad/CTRPv2.0_2015_ctd2_ExpandedDataset).SangerGDSCdrugsensitivity(AUCandIC50scores)weredownloadedfromtheSangerwebsite(https://www.cancerrxgene.org/downloads). Codeavailability MostofthestatisticalanalyseswereperformedinR(version3.5.2).Sourcecodesareavailableuponrequest. ReferencesBarretina,J.etal.TheCancerCellLineEncyclopediaenablespredictivemodellingofanticancerdrugsensitivity.Nature483,603–607(2012).CAS  ADS  Article  GoogleScholar  Li,H.etal.Thelandscapeofcancercelllinemetabolism.Nat.Med.https://doi.org/10.1038/s41591-019-0404-8(2019).Iorio,F.etal.Alandscapeofpharmacogenomicinteractionsincancer.Cell166,740–754(2016).CAS  Article  GoogleScholar  Ben-David,U.etal.Geneticandtranscriptionalevolutionalterscancercelllinedrugresponse.Nature560,325–330(2018).CAS  ADS  Article  GoogleScholar  Tsherniak,A.etal.DefiningacancerdependencyMap.Cell170,564–576(2017).CAS  Article  GoogleScholar  McDonald,E.R.IIIetal.ProjectDRIVE:acompendiumofcancerdependenciesandsyntheticlethalrelationshipsuncoveredbylarge-scale,deepRNAiscreening.Cell170,577–592(2017).Article  GoogleScholar  Meyers,R.M.etal.ComputationalcorrectionofcopynumbereffectimprovesspecificityofCRISPR–Cas9essentialityscreensincancercells.Nat.Genet.49,1779–1784(2017).CAS  Article  GoogleScholar  Huang,F.W.etal.HighlyrecurrentTERTpromotermutationsinhumanmelanoma.Science339,957–959(2013).CAS  ADS  Article  GoogleScholar  Diouf,B.etal.SomaticdeletionsofgenesregulatingMSH2proteinstabilitycauseDNAmismatchrepairdeficiencyanddrugresistanceinhumanleukemiacells.Nat.Med.17,1298–1303(2011).CAS  Article  GoogleScholar  Marra,G.etal.MismatchrepairdeficiencyassociatedwithoverexpressionoftheMSH3gene.Proc.NatlAcad.Sci.USA95,8568–8573(1998).CAS  ADS  Article  GoogleScholar  Esakova,O.&Krasilnikov,A.S.OfproteinsandRNA:theRNaseP/MRPfamily.RNA16,1725–1747(2010).CAS  Article  GoogleScholar  Hands-Taylor,K.L.etal.HeterodimerizationofthehumanRNaseP/MRPsubunitsRpp20andRpp25isaprerequisiteforinteractionwiththeP3armofRNaseMRPRNA.NucleicAcidsRes.38,4052–4066(2010).CAS  Article  GoogleScholar  Doherty,J.R.&Cleveland,J.L.Targetinglactatemetabolismforcancertherapeutics.J.Clin.Invest.123,3685–3692(2013).CAS  Article  GoogleScholar  Herman,J.G.etal.SilencingoftheVHLtumor-suppressorgenebyDNAmethylationinrenalcarcinoma.Proc.NatlAcad.Sci.USA91,9700–9704(1994).CAS  ADS  Article  GoogleScholar  Jaffe,J.D.etal.GlobalchromatinprofilingrevealsNSD2mutationsinpediatricacutelymphoblasticleukemia.Nat.Genet.45,1386–1391(2013).CAS  Article  GoogleScholar  Creech,A.L.etal.BuildingtheConnectivityMapofepigenetics:chromatinprofilingbyquantitativetargetedmassspectrometry.Methods72,57–64(2015).CAS  Article  GoogleScholar  Sveen,A.,Kilpinen,S.,Ruusulehto,A.,Lothe,R.A.&Skotheim,R.I.AberrantRNAsplicingincancer;expressionchangesanddrivermutationsofsplicingfactorgenes.Oncogene35,2413–2427(2016).CAS  Article  GoogleScholar  Dewaele,M.etal.Antisenseoligonucleotide-mediatedMDM4exon6skippingimpairstumorgrowth.J.Clin.Invest.126,68–84(2016).Article  GoogleScholar  Rallapalli,R.,Strachan,G.,Cho,B.,Mercer,W.E.&Hall,D.J.AnovelMDMXtranscriptexpressedinavarietyoftransformedcelllinesencodesatruncatedproteinwithpotentp53repressiveactivity.J.Biol.Chem.274,8299–8308(1999).CAS  Article  GoogleScholar  Gembarska,A.etal.MDM4isakeytherapeutictargetincutaneousmelanoma.Nat.Med.18,1239–1247(2012).CAS  Article  GoogleScholar  Boutz,P.L.,Bhutkar,A.&Sharp,P.A.Detainedintronsareanovel,widespreadclassofpost-transcriptionallysplicedintrons.GenesDev.29,63–80(2015).Article  GoogleScholar  Maruvka,Y.E.etal.Analysisofsomaticmicrosatelliteindelsidentifiesdrivereventsinhumantumors.Nat.Biotechnol.35,951–959(2017).CAS  Article  GoogleScholar  Zhang,Y.etal.RibosomalproteinsRpl22andRpl22l1controlmorphogenesisbyregulatingpre-mRNAsplicing.CellReports18,545–556(2017).CAS  Article  GoogleScholar  Lu,J.etal.MicroRNAexpressionprofilesclassifyhumancancers.Nature435,834–838(2005).CAS  ADS  Article  GoogleScholar  Li,J.etal.Characterizationofhumancancercelllinesbyreverse-phaseproteinarrays.CancerCell31,225–239(2017).CAS  Article  GoogleScholar  Chen,Y.N.etal.AllostericinhibitionofSHP2phosphataseinhibitscancersdrivenbyreceptortyrosinekinases.Nature535,148–152(2016).CAS  ADS  Article  GoogleScholar  Wylie,A.A.etal.TheallostericinhibitorABL001enablesdualtargetingofBCR–ABL1.Nature543,733–737(2017).CAS  ADS  Article  GoogleScholar  Haibe-Kains,B.etal.Inconsistencyinlargepharmacogenomicstudies.Nature504,389–393(2013).CAS  ADS  Article  GoogleScholar  TheCancerCellLineEncyclopediaConsortium&TheGenomicsofDrugSensitivityinCancerConsortium.Pharmacogenomicagreementbetweentwocancercelllinedatasets.Nature528,84–87(2015).ADS  Article  GoogleScholar  Haverty,P.M.etal.Reproduciblepharmacogenomicprofilingofcancercelllinepanels.Nature533,333–337(2016).CAS  ADS  Article  GoogleScholar  Geeleher,P.,Gamazon,E.R.,Seoighe,C.,Cox,N.J.&Huang,R.S.Consistencyinlargepharmacogenomicstudies.Nature540,E1–E2(2016).CAS  ADS  Article  GoogleScholar  Bouhaddou,M.etal.DrugresponseconsistencyinCCLEandCGP.Nature540,E9–E10(2016).CAS  Article  GoogleScholar  Mpindi,J.P.etal.Consistencyindrugresponseprofiling.Nature540,E5–E6(2016).CAS  Article  GoogleScholar  Yu,C.etal.High-throughputidentificationofgenotype-specificcancervulnerabilitiesinmixturesofbarcodedtumorcelllines.Nat.Biotechnol.34,419–423(2016).CAS  Article  GoogleScholar  King,A.J.etal.Abstract2116:Combiningthepowerofdifferentprofilingapproachestobetterunderstandtheactivityofkinaseinhibitordrugs.CancerRes.77,2116–2116(2017). GoogleScholar  Fisher,S.etal.Ascalable,fullyautomatedprocessforconstructionofsequence-readyhumanexometargetedcapturelibraries.GenomeBiol.12,R1(2011).Article  GoogleScholar  Johannessen,C.M.etal.AmelanocytelineageprogramconfersresistancetoMAPkinasepathwayinhibition.Nature504,138–142(2013).CAS  ADS  Article  GoogleScholar  Boyle,P.etal.Gel-freemultiplexedreducedrepresentationbisulfitesequencingforlarge-scaleDNAmethylationprofiling.GenomeBiol.13,R92(2012).CAS  Article  GoogleScholar  Brat,D.J.etal.Comprehensive,integrativegenomicanalysisofdiffuselower-gradegliomas.N.Engl.J.Med.372,2481–2498(2015).CAS  Article  GoogleScholar  CancerGenomeAtlasResearchNetwork.Integratedgenomiccharacterizationofpapillarythyroidcarcinoma.Cell159,676–690(2014).Article  GoogleScholar  Huang,F.W.etal.TERTpromotermutationsandmonoallelicactivationofTERTincancer.Oncogenesis4,e176(2015).CAS  Article  GoogleScholar  Cibulskis,K.etal.Sensitivedetectionofsomaticpointmutationsinimpureandheterogeneouscancersamples.Nat.Biotechnol.31,213–219(2013).CAS  Article  GoogleScholar  Lek,M.etal.Analysisofprotein-codinggeneticvariationin60,706humans.Nature536,285–291(2016).CAS  Article  GoogleScholar  VanderAuwera,G.A.etal.FromFastQdatatohighconfidencevariantcalls:theGenomeAnalysisToolkitbestpracticespipeline.Curr.Protoc.Bioinformatics43,11.10.11–11.10.33(2013). GoogleScholar  Wala,J.A.etal.SvABA:genome-widedetectionofstructuralvariantsandindelsbylocalassembly.GenomeRes.28,581–591(2018).CAS  Article  GoogleScholar  Haas,B.etal.STAR-Fusion:fastandaccuratefusiontranscriptdetectionfromRNA-seq.Preprintat https://www.bioRxiv.org/content/10.1101/120295v1(2017).Kasar,S.etal.Whole-genomesequencingrevealsactivation-inducedcytidinedeaminasesignaturesduringindolentchroniclymphocyticleukaemiaevolution.Nat.Commun.6,8866(2015).CAS  Article  GoogleScholar  Kim,J.etal.SomaticERCC2mutationsareassociatedwithadistinctgenomicsignatureinurothelialtumors.Nat.Genet.48,600–606(2016).CAS  Article  GoogleScholar  TheCancerGenomeAtlasResearchNetwork.Comprehensiveandintegratedgenomiccharacterizationofadultsofttissuesarcomas.Cell171,950–965(2017).Article  GoogleScholar  Haradhvala,N.J.etal.Distinctmutationalsignaturescharacterizeconcurrentlossofpolymeraseproofreadingandmismatchrepair.Nat.Commun.9,1746(2018).CAS  ADS  Article  GoogleScholar  Carter,S.L.etal.AbsolutequantificationofsomaticDNAalterationsinhumancancer.Nat.Biotechnol.30,413–421(2012).CAS  Article  GoogleScholar  Krueger,F.&Andrews,S.R.Bismark:aflexiblealignerandmethylationcallerforBisulfite-Seqapplications.Bioinformatics27,1571–1572(2011).CAS  Article  GoogleScholar  Akalin,A.etal.methylKit:acomprehensiveRpackagefortheanalysisofgenome-wideDNAmethylationprofiles.GenomeBiol.13,R87(2012).Article  GoogleScholar  Ziller,M.J.etal.ChartingadynamicDNAmethylationlandscapeofthehumangenome.Nature500,477–481(2013).CAS  ADS  Article  GoogleScholar  vanderMaaten,L.&Hinton,G.Visualizinghigh-dimensionaldatausingt-SNE.J.Mach.Learn.Res.9,2579–2605(2008).MATH  GoogleScholar  Szklarczyk,D.etal.STRINGv10:protein-proteininteractionnetworks,integratedoverthetreeoflife.NucleicAcidsRes.43,D447–D452(2015).CAS  Article  GoogleScholar  Cerami,E.etal.ThecBiocancergenomicsportal:anopenplatformforexploringmultidimensionalcancergenomicsdata.CancerDiscov.2,401–404(2012).Article  GoogleScholar  Gao,J.etal.IntegrativeanalysisofcomplexcancergenomicsandclinicalprofilesusingthecBioPortal.Sci.Signal.6,pl1(2013).Article  GoogleScholar  Dobin,A.etal.STAR:ultrafastuniversalRNA-seqaligner.Bioinformatics29,15–21(2013). GoogleScholar  DeLuca,D.S.etal.RNA-SeQC:RNA-seqmetricsforqualitycontrolandprocessoptimization.Bioinformatics28,1530–1532(2012).CAS  Article  GoogleScholar  GTExConsortium.Geneticeffectsongeneexpressionacrosshumantissues.Nature550,204–213(2017).Article  GoogleScholar  Ritchie,M.E.etal.limmapowersdifferentialexpressionanalysesforRNA-sequencingandmicroarraystudies.NucleicAcidsRes.43,e47(2015).Article  GoogleScholar  Smyth,G.K.LinearmodelsandempiricalBayesmethodsforassessingdifferentialexpressioninmicroarrayexperiments.Stat.Appl.Genet.Mol.Biol.3,1–25(2004).Akbani,R.etal.Apan-cancerproteomicperspectiveonTheCancerGenomeAtlas.Nat.Commun.5,3887(2014).CAS  Article  GoogleScholar  Friedman,J.,Hastie,T.&Tibshirani,R.Regularizationpathsforgeneralizedlinearmodelsviacoordinatedescent.J.Stat.Softw.33,1–22(2010).Article  GoogleScholar  DownloadreferencesAcknowledgementsWethanktheBroadGenomicsPlatform,C.Clish,H.Bitter,A.NajafiandE.Orlandofortheircontribution.ThisworkwassupportedbygrantsfromNovartisandpartiallybyNIH/NCIgrants1U01CA217842-01,1P50CA217685-01,5P50CA098258,1U24CA180922-01,1R50CA211461-01,CA16672,1R01CA219943-01,1U54CA224068-01,NIHU01CA176058andR21DA025720.F.W.H.wassupportedbytheProstateCancerFoundation.M.I.wassupportedbyaBurroughsWellcomeFundCareerAward.G.G.waspartiallysupportedbythePaulC.Zamecnik,MD,ChairinOncologyatMGH. G.B.M.wassupportedbytheAdelsonmedicalresearchfund.DrugsensitivityresultsareinpartbasedondatageneratedbyCancerTargetDiscoveryandDevelopment(CTD2)Network(https://ocg.cancer.gov/programs/ctd2/data-portal)establishedbytheNationalCancerInstitute’sOfficeofCancerGenomics. Reviewerinformation NaturethanksNevanKrogan,ChristophPlassandtheotheranonymousreviewer(s)fortheircontributiontothepeerreviewofthiswork. AuthorinformationAuthornotesFranklinW.HuangPresentaddress:UniversityofCaliforniaSanFrancisco,SanFrancisco,CA,USADmitriySonkinPresentaddress:NationalCancerInstitute,Rockville,MD,USAWilliamR.SellersPresentaddress:BroadInstituteofHarvardandMIT,Cambridge,MA,USAJordiBarretinaPresentaddress:GironaBiomedicalResearchInstitute(IDIBGI),Girona,SpainTheseauthorscontributedequally:MahmoudGhandi,FranklinW.Huang.Theseauthorsjointlysupervisedthiswork:LeviA.Garraway,WilliamR.Sellers.AuthorsandAffiliationsBroadInstituteofHarvardandMIT,Cambridge,MA,USAMahmoudGhandi, FranklinW.Huang, JuditJané-Valbuena, GregoryV.Kryukov, ChristopherC.Lo, EllenT.Gelfand, CraigM.Bielski, HaoxinLi, KevinHu, AlexanderY.Andreev-Drakhlin, JaegilKim, JulianM.Hess, BrianJ.Haas, FrançoisAguet, BarbaraA.Weir, MichaelV.Rothberg, BrentonR.Paolella, MichaelS.Lawrence, AliAminMansour, CoyinOh, JuliannShih, YanayRosen, JonathanBistline, JordanE.Taylor, CaitlinM.Dunning, AmandaL.Creech, AllisonC.Warren, JamesM.McFarland, MahdiZamanighomi, NicolasStransky, YosefE.Maruvka, AndrewD.Cherniack, AviadTsherniak, FranciscaVazquez, JacobD.Jaffe, CoryM.Johannessen, WilliamC.Hahn, GadGetz, JesseS.Boehm, ToddR.Golub & LeviA.GarrawayDepartmentofMedicalOncology,Dana-FarberCancerInstitute,Boston,MA,USAFranklinW.Huang, JuditJané-Valbuena, HaoxinLi, AndrewD.Cherniack, AndrewA.Lane, DavidM.Weinstock, WilliamC.Hahn, ToddR.Golub & LeviA.GarrawayNovartisInstitutesforBiomedicalResearch,Cambridge,MA,USAE.RobertMcDonaldIII, JordiBarretina, KavithaVenkatesan, AnupamaReddy, DmitriySonkin, ManwayLiu, JosephLehar, JoshuaM.Korn, DaleA.Porter, MichaelD.Jones, JavadGolji, GiordanoCaponigro, MichaelP.Morrissey, FrankStegmeier, RobertSchlegel & WilliamR.SellersMassachusettsGeneralHospitalCancerCenter,Boston,MA,USAMichaelS.Lawrence, YosefE.Maruvka & GadGetzDepartmentofPathology,MassachusettsGeneralHospital,Boston,MA,USAMichaelS.Lawrence & GadGetzHarvardMedicalSchool,Boston,MA,USAMichaelS.Lawrence & GadGetzTheUniversityofTexasMDAndersonCancerCenter,Houston,TX,USARehanAkbani, YilingLu & GordonB.MillsBelferCenterforAppliedCancerScience,Boston,MA,USAHongL.Tiv & PrafullaC.GokhaleNovartisInstitutesforBiomedicalResearch,Basel,SwitzerlandAntoinedeWeck & AudreyKauffmannNewYorkGenomeCenter,NewYork,NY,USAKevinHadi & MarcinImielinskiDepartmentofPathologyandLaboratoryMedicine,EnglanderInstituteforPrecisionMedicine,InstituteforComputationalBiomedicine,andMeyerCancerCenter,WeillCornellMedicine,NewYork,NY,USAKevinHadi & MarcinImielinskiHowardHughesMedicalInstitute,ChevyChase,MD,USAToddR.GolubAuthorsMahmoudGhandiViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarFranklinW.HuangViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJuditJané-ValbuenaViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarGregoryV.KryukovViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarChristopherC.LoViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarE.RobertMcDonaldIIIViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJordiBarretinaViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarEllenT.GelfandViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarCraigM.BielskiViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarHaoxinLiViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarKevinHuViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAlexanderY.Andreev-DrakhlinViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJaegilKimViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJulianM.HessViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarBrianJ.HaasViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarFrançoisAguetViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarBarbaraA.WeirViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarMichaelV.RothbergViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarBrentonR.PaolellaViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarMichaelS.LawrenceViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarRehanAkbaniViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarYilingLuViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarHongL.TivViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarPrafullaC.GokhaleViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAntoinedeWeckViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAliAminMansourViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarCoyinOhViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJuliannShihViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarKevinHadiViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarYanayRosenViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJonathanBistlineViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarKavithaVenkatesanViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAnupamaReddyViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarDmitriySonkinViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarManwayLiuViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJosephLeharViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJoshuaM.KornViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarDaleA.PorterViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarMichaelD.JonesViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJavadGoljiViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarGiordanoCaponigroViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJordanE.TaylorViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarCaitlinM.DunningViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAmandaL.CreechViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAllisonC.WarrenViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJamesM.McFarlandViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarMahdiZamanighomiViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAudreyKauffmannViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarNicolasStranskyViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarMarcinImielinskiViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarYosefE.MaruvkaViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAndrewD.CherniackViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAviadTsherniakViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarFranciscaVazquezViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJacobD.JaffeViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarAndrewA.LaneViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarDavidM.WeinstockViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarCoryM.JohannessenViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarMichaelP.MorrisseyViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarFrankStegmeierViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarRobertSchlegelViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarWilliamC.HahnViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarGadGetzViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarGordonB.MillsViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarJesseS.BoehmViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarToddR.GolubViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarLeviA.GarrawayViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarWilliamR.SellersViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarContributionsFortheworkdescribedherein,M.G.,F.W.H.,G.V.K.,E.R.M.,J.B.,G.C.,N.S.,J.D.J.,A.A.L.,C.M.J.,M.P.M.,F.S.,R.S.,W.C.H.,T.R.G.,L.A.G.andW.R.S.conceivedthestudies;M.G.,G.V.K.,C.C.L.,C.M.B.,H.L.,K. Hu,J.K.,J.M.H.,B.J.H.,F.A.,B.A.W.,M.S.L.,R.A.,A.D.,A.A.M.,C.O.,J.S.,K. Hadi,K.V.,A.R.,D.S.,M.L.,J.L.,J.M.K.,M.D.J.,J.G.,A.C.W.,J.M.M.,M.Z.,A.K.,N.S.,M.I.,Y.E.M.,A.D.C.,A.T.andG.G.performedcomputationalbiologyanalysis;F.W.H.,J.J.-V.,E.R.M.,J.B.,A.Y.A.-D.,M.V.R.,B.R.P.,Y.L.,H.L.T.,P.C.G.,D.A.P.,G.C.,J.E.T.,C.M.D.,A.L.C.,F.V.,J.D.J.,A.A.L.,C.M.J.andF.S.performedbiologicalanalysisandinterpretation;M.G.,G.V.K.,Y.R.andJ.B.contributedtosoftwaredevelopment;M.G.,F.W.H.,J.J.-V.,G.V.K.,C.C.L.,H.L.,K. Hu,A.Y.A.-D.,M.V.R.,R.A.,H.L.T.andK. HadipreparedfiguresandtablesforthemaintextandSupplementaryInformation;M.G.,F.W.H.,J.J.-V.andW.R.S.wrotethepaper;E.R.M.,J.B.,M.V.R.,B.R.P.,R.A.,P.C.G.,A.K.,A.T.,A.A.L.,D.M.W.,R.S.,W.C.H.,G.B.M.,J.S.B.andL.A.G.commentedonandeditedthemanuscript;E.T.G.performedprojectmanagement;D.M.W.,M.P.M.,R.S.,W.C.H.,G.G.,G.B.M.,J.S.B.andT.R.G.contributedprojectoversightandadvisoryroles;M.G.andG.V.K.weretheleadcomputationalbiologists;F.S.,L.A.G.andW.R.S.providedoverallprojectleadershipanddevelopedtheconceptsandstrategyfortheproject;L.A.G.andW.R.S.weretheseniorauthors.CorrespondingauthorCorrespondenceto WilliamR.Sellers.Ethicsdeclarations Competinginterests J.M.K.,M.D.J.,D.A.P.,F.S.,E.R.M.,J.L.,R.S.,J.B.,A.D.,K.V.,A.R.,J.G.,G.C.,M.L.,A.K.,M.P.M.andW.R.S.arecurrentorformerNovartisemployeesand/orstockholders.W.R.S.isaBoardorSABmemberandholdsequityinPelotonTherapeuticsandIdeayaBiosciencesandhasconsultedforArray,Astex,Ipsen,SanofiandServier.B.A.W.isaJ&Jemployee.F.S.andG.V.K.areKSQTherapeuticsemployees.N.S.isanemployeeofCelsiusTherapeutics.A.D.C.receivesresearchsupportfromBayerAG. G.G.receivesresearchsupportfromIBMandPharmacyclicsandisaninventoronpatentapplicationsrelatedtoMuTectandABSOLUTE.G.B.M.consultswithAstraZeneca,ImmunoMET,Ionis,Nuevolution,PDXBio,SignalchemLifesciences,Symphogen andTarveda,hasstockoptionswithCatenaPharmaceuticals,ImmunoMet,SignalChem,SpindleTopVenturesandTarveda,hassponsoredresearchfundingfromAdelsonMedicalResearchFoundation,AstraZeneca,BreastCancerResearchFoundation,Immunomet,KomenResearchFoundation,Pfizer,Nanostring,Tesaro,travelsupportfromChrysallisBio andhaslicensedtechnologytoNanostringandMyriadGenetics.T.R.G.isanadvisortoGlaxoSmithKline,isaco-founderofSherlockBiosciences andwasaco-founderandadvisortoFoundationMedicine.J.K.isaTesaroemployee.W.C.H.isaconsultantforThermoFisher,AjuIB,ParaxelandMPMCapital,andisafounderandconsultantforKSQTherapeutics.L.A.G.isanemployeeofEliLilly. AdditionalinformationPublisher’snote:SpringerNatureremainsneutralwithregardtojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations.ExtendeddatafiguresandtablesExtendedDataFig.1OverviewofCCLEcelllinesanddatasets.a,TheexistingandnewCCLEdatasetsasindicatedaredepicted.b,DistributionofcelllinesbylineageandancestryacrossCCLE.c,Visualrepresentationofthenumberofcelllinesineachdataset.NewCCLEdatasetsareshowninred.Functionalgenomicsdatasetsareshowninblue.ExtendedDataFig.2CCLEvariantcallingpipelineandCCLEandGDSCcomparison.a,Unifiedpipelineintegratingmutationandindelcallsfromdifferentplatformswasusedtogenerateasetofhighconfidencegenomicalterationsacross1,063cancercelllines.Identifiedvariantswerecross-referencedwiththeExACandTCGAdatabasesandapanelofnormals(PoN)toexcludegermlinevariants/artefactsandgeneratethefinalizedhigh-confidencevariantcallset.b–d,ComparisonofvariantcallsbetweenCCLEandSangerGDSCcelllinesforgermline(b;n = 1,250,562),TCGAhotspotsomatic(c;n = 281)andnon-hotspotsomatic(d;n = 82,572)variantsusingWESdata.Pearson’scorrelationcoefficientsareshown.e,ComparisonofTCGAhotspotvariantcallsbetweenCCLEHybridCapture(HC)dataandSangerGDSCWESdata.Variantswithallelicfraction>0.4inonedatasetandgreaterthanfourfolddifferenceinallelicfractionsbetweenthetwodatasetsareshownasopencircles(n = 980).f,g,ComparisonofPearson’scorrelationcoefficientsbetweenCCLEWESandSangerGDSCWESdataversusPearson’scorrelationcoefficientsbetweenCCLEHCandSangerGDSCWESdataforgermline(f;n = 107)andsomatic(g;n = 93)variants.Celllineswithfewerthan30variantswereexcluded.h,ComparisonofallelicfractionPearson’scorrelationsbetweenCCLEcelllinesandSangercelllinesusingCCLEHCandSangerGDSCWESdata(n = 558commoncelllinesbetweenthetwodatasets;SupplementaryTable3).Celllineswithlowgermlinecorrelation(samplemismatch)andlowsomaticcorrelation(geneticdrift)arehighlighted.ExtendedDataFig.3AnnotationofstructuralvariantsandfusionsinCCLEcelllines.a,StructuralvariantburdeninCCLEwholegenomes.StructuralvariantsdetectedbySvABAincelllinesgroupedbytissuetypeareplottedintheorderofmeanstructuralvariantburden(redbarineachfacet).b,BarplotofrecurrentCOSMICfusionsdetectedinCCLERNA-seqdatacolouredbycelllinelineage.c,VolcanoplotofAchillesRNAigenedependenciesversusCCLEfusionsforcelllines(n = 478)commonbetweenCCLEandAchillesdatasets.Pvaluesdeterminedbytwo-sidedt-test.GeneswithsignificantadjustedP values(falsediscoveryrate(FDR) 6or|z2| > 6arehighlighted.c,DistributionofPearson’scorrelationsofmir-215expressionwithAchillesRNAigenedependenciesfor16,871genes(n = 162–420celllines;SupplementaryTable13).CTNNB1knockdownisthetopnegativecorrelatewithmir-215expression.d,DistributionofPearson’scorrelationsofCTNNB1genedependencywithall734measuredmiRNAs(n = 420celllines).Theexpressionofmir-215isthetopgenenegativelycorrelatedwithCTNNB1dependency.mir-215andmir-194-1clustertogetherat1q41,whereasmir-192andmir-194-2clusterat11q13.1.mir-215andmir-192areclosehomologues.e,Scatterplotofmir-215expressionversusCTNNB1dependencyofallCCLEcelllines.Colonandstomachlineagesareshowninblueandred,respectively.f,Scaledmir-215expressioninTCGAandCCLEdatasets(n = 14;mean ± s.e.m.).Stomachandcolorectallineagesinbothdatasetshavehighmir-215expression.g,Single-samplegenesetenrichmentanalysisidentifiesTGFB1andWNT3Apathwaygenesetscorrelatedwithmir-215expressionusingCCLERNA-seqdata.Thegeneset‘LabbetargetsofTGFB1andWNT3A’ofdownstreamtargetsofTGF-βandWNTligandsisnegativelycorrelatedwithmir-215expression.h,Thegeneset‘LabbetargetsofTGFB1andWNT3A’isnegativelycorrelatedwithmir-215expressionintheTCGAstomachmRNAexpressiondataset.i,Thegeneset‘Vecchigastricadvancedvsearlydn’ofdownregulatedgenesdistinguishingbetweenadvancedandearlygastriccancersubtypesispositivelycorrelatedwithmir-215expressionintheCCLE.j,mir-215expressioninthestomachTCGAmRNAexpressiondatasetispositivelycorrelatedwiththe‘Vecchigastricadvancedvsearlydn’geneset.ExtendedDataFig.11RPPAanalysis.a,DistributionofPearson’scorrelationcoefficientbetweentotalproteinlevelsasmeasuredbyRPPAandmRNAexpressionlevelsmeasuredbyRNA-seq(n = 890celllines,154genes).TheempiricalnulldistributionforcorrelationofmRNAandproteinfortworandomgenesisshownforcomparison(P