RESEARCHARTICLESUMMARY◥CANCERGENOMICSDecouplinggenetics,lineages,andmicroenvironmentinIDH-mutantgliomasbysingle-cellRNA-seqAndrewS.Venteicher,*ItayTirosh,*†ChristineHebert,KerenYizhak,CyrilNeftel,MariellaG.Filbin,VolkerHovestadt,LeahE.Escalante,McKenzieL.Shaw,ChristopherRodman,ShawnM.Gillespie,DanielleDionne,ChristinaC.Luo,HiranmayiRavichandran,RavindraMylvaganam,ChristopherMount,MaristelaL.Onozato,BrianV.Nahed,HiroakiWakimoto,WilliamT.Curry,A.JohnIafrate,MiguelN.Rivera,MatthewP.Frosch,ToddR.Golub,PriscillaK.Brastianos,GadGetz,AnoopP.Patel,MichelleMonje,DanielP.Cahill,OritRozenblatt-Rosen,DavidN.Louis,BradleyE.Bernstein,AvivRegev,†‡MarioL.Suvà†‡INTRODUCTION:Tumorfitness,evolution,andresistancetotherapyaregovernedbyselec-tionofmalignantcellswithspecificgenotypes,byexpressionprogramsrelatedtocellularpheno-types,andbyinfluencesofthetumormicroen-vironment(TME).Althoughbulktumoranalysiscaninterrogatethegeneticstateoftumorcellswithhighprecision,bulkexpressionprofilesaver-agethediversecellswithineachtumor,therebymaskingcriticaldifferencesandprovidinglim-itedinsightintocancercellprogramsandTMEinfluences.Single-cellRNAsequencing(scRNA-seq)canhelptoaddressthosechallengesbutincursfinancialandlogisticconsiderations,in-cludingthetimerequiredtoaccruelargecohortsoffreshtumorspecimenforsingle-cellanalysis.RATIONALE:WereasonedthatscRNA-seqofalimitednumberofrepresentativetumorscouldbecombinedwithbulkdatafromlargecohortstodecipherdifferencesbetweentumorsubclasses.Inthisapproach,bulksamplescollectedforlargecohorts,suchasfromTheCancerGenomeAtlas(TCGA),arefirstusedtodefinethecombinedeffectsofdifferencesincancercellgenotypes,phenotypes,andthecompositionoftheTME.Single-cellanalysisofalimitedsetofrepresenta-tivetumorsisthenusedtodistinguishthoseef-fects.Weappliedthisapproachtounderstandthedifferencesbetweentwotypesofisoci-tratedehydrogenase(IDH)–mutantgliomas:astrocytoma(IDH-A)andoligodendroglioma(IDH-O).IDH-AandIDH-Oaredistinguishedbyco-occurringsignaturege-neticeventsandbyhisto...
