biostudies-literatureBiswas DAustrian Science Fund FWFCancer Research UKInternational Association for the Study of Lung Cancer (IASLC)Hungarian Academy of Sciences | Magyar Tudományos Akadémia Számítástechnikai és Automatizálási Kutatóintézet (Számítástechnikai és Automatizálási Kutatóintézet)Japan Society for the Promotion of Science London (JSPS London)The Francis Crick InstituteUniversity College London (UCL)Wellcome TrustNovo Nordisk Foundation Center for Basic Metabolic Research (NovoNordisk Foundation Center for Basic Metabolic Research)86-101https://www.ebi.ac.uk/biostudies/studies/S-EPMC11779643biostudies-literatureUnknown6(1)Human tumors are diverse in their natural history and response to treatment, which in part results from genetic and transcriptomic heterogeneity. In clinical practice, single-site needle biopsies are used to sample this diversity, but cancer biomarkers may be confounded by spatiogenomic heterogeneity within individual tumors. Here we investigate clonally expressed genes as a solution to the sampling bias problem by analyzing multiregion whole-exome and RNA sequencing data for 450 tumor regions from 184 patients with lung adenocarcinoma in the TRACERx study. We prospectively validate the survival association of a clonal expression biomarker, Outcome Risk Associated Clonal Lung Expression (ORACLE), in combination with clinicopathological risk factors, and in stage I disease. We expand our meNature cancerProspective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma.PMC11779643UCL/12/0279CC2088202060447C11496/A17786, C416/A21999220589/Z/20/ZCC1064CC2040CC2041Young Investigator GrantID16584CTUQQR-DEC22/100009EDDCPJT\100008I4677Bolyai Research ScholarshipLitovchenko MOsman ABailey CStavrou GAtkin AStephens RCMFraioli FStone RKThakrar RMPilotti CBiswas DSivakumar MPrymas PMcGranahan NZaidi RThol KLiu YHAlzetani ABrown KDYuan YLindberg AHackshaw ADe Sousa PChavan HWilson GARowan AAsif MChaturvedi AGronroos ELangman GRussell PFennell DANaito YEast PMartinez-Ruiz CForster MDMalima MKerr KMNovasio JKhiroya RShackleford HSummers YBenafif SNicod JWatkins TBKVeeriah SLee SMGrapa AMussa BLeonce DBishop PKaplar ZDwornik AUsaite IBola SKLe Quesne JDjearaman MBlack JRMDownward JPaiva-Correia AHill WBajaj APatrini DSpanswick VColliver EPich OKostoulas NTugwood JCarter MAbdulJabbar KBlyth KGBakir MADemeulemeester JProli CFernandes NCollins-Fekete CARathinam STaylor MNEscudero MGilbert KPawlik PJanes SMBegum SDome BSzallasi ZSwanton CSangha MChuter DBhayani HBoeing SRammohan KLindsay CRLu WTMoore DALiu WKKhalil MMonk FPatel AJNaceur-Lombardelli CToncheva AJordan SScott RShackcloth MJRane JKKoh KAngelova MChee SHerrero JHobson PKassiotis GKidd AGrigoriadis KMalhi ABoleti EMoldvay JOliveira PLim EScotland MKaufmann TLDulloo SShah MPapadatos-Pastos DBandula SShah PHiley CTZhang HWilson JWhiteley JCrosbie PBilancia RQuezada SALeek ALeslie RGoldman JSahai ETotton NWeeden CERoyle GLucas OBhakhri KPisciella MCAhmed ASelvaraju KGorman PTufail MWaplington SRichardson SBeck SFontaine EWong YNSHacker AMCastignani CMegyesfalvi ZKanu NMurphy CKaniu DCheyne HSaghafinia SChoudhary JRice ADanson SBunkum ADive CSchwarz RFMacKenzie MHarries SJones TPHolding JWReading JLKeene EHewish MHessey SDick CLee CZagorulya MHartley JAGeorg PThomas MPearce DRNavani NMatharu GVeiga CBooth SLester JFNicholson AGKirk APrice GNoorani IKittel JBuderi SIKaramani ARichard CAshford PFalzon MWilson CSnell DMBirkbak NJUng SKACave JNakas AKaragianni DLeung MMZaccaria SBarbe VSodha-Ramdeen AKarasaki TMastrokalos GTPatruno LAhmad TAerts HJWLO'Neill OMiddleton GMarafioti TEnfield KSSEnsell LHodgkinson JDWu YMicke PShaw JAPuttick CBlackhall FHLowe HLGimeno-Valiente FMagala MProcter AJJamal-Hanjani MHaase KVendramin Rde Carne Trecesson SKrebs MGGamble SPeggs KSBentham RRamsden ZRaubenheimer HChain BHuebner ARosenthal RVan Loo PMagno NFrench JNaidu BWard SHill MSWalker AJoshi VThakkar KDenner TLawrence DFrankell AMBoyles RVanloo SPan XTRACERx ConsortiumRobinson LHoogenboom EMAmbrose LDevaraj ADiossy MJoseph LFillinger JGranato FSmith SBorg ESalgado RMattsson JNye ELim ELCruickshank TNair AfalseProspective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma.Human tumors are diverse in their natural history and response to treatment, which in part results from genetic and transcriptomic heterogeneity. In clinical practice, single-site needle biopsies are used to sample this diversity, but cancer biomarkers may be confounded by spatiogenomic heterogeneity within individual tumors. Here we investigate clonally expressed genes as a solution to the sampling bias problem by analyzing multiregion whole-exome and RNA sequencing data for 450 tumor regions from 184 patients with lung adenocarcinoma in the TRACERx study. We prospectively validate the survival association of a clonal expression biomarker, Outcome Risk Associated Clonal Lung Expression (ORACLE), in combination with clinicopathological risk factors, and in stage I disease. We expand our me2025-01-01T00:00:00Z2025 Jan2026-06-01T20:07:23.595Z2025-04-04T14:05:48.412ZS-EPMC117796433978917910.1038/s43018-024-00883-1