biostudies-literatureKarasaki TCancer Research UKThe Francis Crick InstituteMedical Research CouncilNational Institute for Health Research (NIHR)RosetreesNCI NIH HHSWellcome Trust833-845https://www.ebi.ac.uk/biostudies/studies/S-EPMC7614478biostudies-literatureUnknown29(4)Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly hiNature medicineEvolutionary characterization of lung adenocarcinoma morphology in TRACERx.PMC7614478R01 CA21716924956CC2088MR/W011786/117786P30 CA008748CC2041RCCFEL\10009929569MR/V033077/1RCCCDF-Nov21\100005C7893/A2623330025FC001202FC001169CC1107MR/P014712/1211179/Z/18/ZCC1062M781CC1061R01 CA240472CTRNBC-2022/100001CC1064CF-2021-2 117CL-2015-18-009R01 CA235667S_360921999CTUQQR-DEC22/100009R01 CA236615CC1119C416/A21999C444/A15953C69256/A30194PGL21 10119CC2008U01 CA214195C11496/A17786C11496/A30025EDDCPGM\100002Osman ALitovchenko MBailey CStavrou GKilgour EFraioli FStone RKThakrar RMPilotti CBiswas DSivakumar MDhanda HKMcGranahan NPrymas PIngram PThol KAlzetani AYuan YDuran MVHackshaw AAl-Sawaf ODe Sousa PChavan HWilson GARowan AAsif MChaturvedi AGronroos EScarci MLangman GRussell PSunderland MWStephens RCFennell DAAthanasopoulou FNaito YLevi DMartinez-Ruiz CLopez SForster MDGomes FMalima MKerr KMNovasio JKhiroya RShackleford HSummers YBenafif SWatkins TBKNicod JVeeriah SLee SMLitchfield KGrapa ABishop PBola SKHoxha ELe Quesne JDjearaman MAdusumilli PSBlack JRMTan KSGower NHill WBajaj APatrini DSpanswick VPich OColliver ETanic MKostoulas NTugwood JCarter MAbdulJabbar KAng KBlyth KGBakir MADemeulemeester JChen KProli CFernandes NMagness ACollins-Fekete CARathinam STaylor MNEscudero MChowdhry MFGilbert KPawlik PScarlett LJanes SMBegum SSzallasi ZSwanton CSharp AKisistok JChuter DBhayani HBoeing SRammohan KLindsay CRLu WTMoore DAKhalil MLiu WKMonk FPatel AJNaceur-Lombardelli CMarrone DToncheva AJordan SShackcloth MJRane JKAngelova MMoss SChee SHerrero JKassiotis GHobson PGrigoriadis KBoleti EOliveira PLeung MLim EScotland MKaufmann TLDulloo SShah MPapadatos-Pastos DBandula SShah PHiley CTShah RZhang HLacson CWilson JCrosbie PBilancia RLeek AQuezada SALeslie RSanchez-Vega FGoldman JWeeden CERoyle GLucas OAhmed ABhakhri KKerr AStewart ASelvaraju KGorman PTufail MRichardson SBeck SFontaine EWong YNSChan KMontero AHayward MCastignani CKanu NMastrokalos GKaniu DCheyne HGalvez-Cancino FSaghafinia SChoudhary JRice AClark TClipson ADanson SDive CBunkum ASchwarz RFDijkstra KMacKenzie MHolding JWReading JLTotten NCampbell BBHewish MDietzen MHessey SRekhtman NDick CLee CHartley JAThomas MJones DRPearce DRNavani NAbbosh CMatharu GRiley JVeiga CBooth STravis WDLester JFNicholson AGKirk APrice GBuderi SINg KWKaramani APanagiotopoulos NRichard CAshford PFalzon MWilson CKadiri SBirkbak NJUng SKACave JNakas AKaragianni DZaccaria SBarbe VAustin SRothwell DGSodha-Ramdeen AKarasaki TAhmad TRichards JAerts HJWLMiddleton GMarafioti TEnfield KSSEnsell LHodgkinson JDSokac MWu YMatos IGCheema WShaw JAPuttick CPrimrose LBlackhall FHLowe HLGimeno-Valiente FProcter AJJamal-Hanjani MHynds REVendramin RDoran HKrebs MGPeggs KSGamble SMourikis TPBentham RRamsden ZRaubenheimer HChain BHuebner ARosenthal RVan Loo PMagno NCadieux ELNaidu BWard SLam JMHill MSChervova OJoshi VThakkar KDenner TLawrence DFrankell AMBoyles RPriest LVanloo SPan XTRACERx ConsortiumZhai HRobinson LHoogenboom EMSmith EAmbrose LDevaraj ADiossy MJoseph LGranato FSmith SBrown KBorg ESalgado RNye ELim ELCruickshank TNair AfalseEvolutionary characterization of lung adenocarcinoma morphology in TRACERx.Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly hi2023-01-01T00:00:00Z2023 Apr2026-04-08T13:05:10.428Z2026-04-08T02:51:17.709ZS-EPMC76144783704599610.1038/s41591-023-02230-w