Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions.
Mark P PurdueDiptavo DuttaMitchell J MachielaBryan R GormanTimothy WinterDayne OkuharaSara ClelandAida Ferreiro-IglesiasPaul A ScheetAoxing LiuChao WuSamuel O AntwiJames LarkinStênio C ZequiMaxine SunKeiko HikinoAli HajiranKeith A LawsonFlavio Mavignier CárcanoOdile BlanchetBrian ShuchKenneth G NeppleGaëlle MargueDebasish SundiW Ryan DiverMaria A A K FolgueiraAdrie van BokhovenFlorencia NeffaKevin M BrownJonathan N HofmannJongeun RheeMeredith YeagerNathan R ColeBelynda D HicksMichelle R ManningAmy A HutchinsonNathaniel RothmanWen-Yi HuangW Marston LinehanAdriana LoriMatthieu FerraguMerzouka Zidane-MarinnesSérgio V SerranoWesley J Magnabosconull nullAna VilasRicardo DeciaFlorencia CarussoLaura S GrahamKyra AndersonMehmet A BilenCletus ArcieroIsabelle PellegrinSolène Ricardnull nullGhislaine SceloRosamonde E BanksNaveen S VasudevNaeem SoomroGrant D StewartAdebanji AdeyojuStephen BromageDavid HroudaNorma GibbonsPoulam Manubhai PatelMark E SullivanAndrew S ProtheroeFrancesca I NugentMichelle J FournierXiaoyu ZhangLisa J MartinMaria KomisarenkoTimothy EisenSonia A CunninghamDenise C ConnollyRobert G UzzoDavid ZaridzeAnush MukeriaIvana HolcatovaAnna HornakovaLenka ForetovaVladimir JanoutDana MatesViorel JingaStefan RascuMirjana MijuskovicSlavisa SavicSasa MilosavljevicValérie GaborieauBehnoush Abedi-ArdekaniJames McKayMattias JohanssonLarry PhouthavongsyLindsay HaymanJason LiIlinca LunguStephania M BezerraAline G SouzaClaudia T G SaresRodolfo B ReisFábio Pescarmona GallucciMauricio D CordeiroMark PomerantzGwo-Shu M LeeMatthew L FreedmanAnhyo JeongSamantha E GreenbergAlejandro SanchezR Houston ThompsonVidit SharmaDavid D ThielColleen T BallDiego AbreuElaine T LamWilliam C NahasViraj A MasterAlpa V PatelJean-Christophe BernhardNeal D FreedmanPierre BigotRui Manuel Vieira ReisLeandro Machado ColliAntonio FinelliBrandon J ManleyChikashi C TeraoToni K ChoueiriDirce M CarraroRichard S HoulstonJeanette E Eckel-PassowPhilip H AbboshAndrea GannaPaul BrennanJian GuStephen J ChanockPublished in: Nature genetics (2024)
Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals.