Abstract LB386: Multi-population GWAS meta-analysis identifies 86 susceptibility regions for renal cell carcinoma

Abstract Renal cell carcinoma (RCC), the predominant form of kidney cancer, represents a significant global health challenge with increasing incidence rates, especially in Western populations. We conducted a multi-population meta-analysis of genome wide association studies including 47,838 cases and 2,578,530 controls across 4 major continental populations. Our analysis reflects an approximate 60% increase in the number of cases with nearly triple the number of non-European RCC cases (N = 9,567) as compared to the previous largest RCC GWAS.We identified 86 autosomal susceptibility regions containing 122 independent risk loci, of which 30 were novel. This included rs10217560 in the 9q24.1 region that increased RCC risk by 28% in African ancestry individuals (odds ratio[OR] = 1.28, 95% confidence interval[CI]: 1.19-1.37) and was not identified in any single study or in other continental populations. We also report the association of rs77804868 in the in the 5′ untranslated region of VHL, previously identified in African ancestry individuals, in admixed American (AMR) individuals as well, which nearly doubles the risk of RCC (ORAMR= 2.17, 95% CI: 1.68-2.80). Fine-mapping identified 2,138 candidate causal variants across the 122 loci which mapped to 210 unique genes through cis-eQTL analysis in kidney tumors of which 16 genes had further evidence from activity-by-contact model based on chromatin state and 3D loops in RCC cell types. Downstream analyses demonstrated an enrichment of accessible chromatin regions in RCC tumors (p = 1.3E-07) and hypoxia-inducible factor-binding sites (p= 4.6E-08) at the identified loci. Transcriptome-wide association studies in normal and tumor kidney tissues identified 197 genes associated with RCC risk of which, 51% did not map to any significant GWAS loci, while proteome-wide association studies identified 13 significant proteins all mapping to GWAS loci. We estimated that the heritability and familial relative risk of RCC attributable to all common variation were 18% (CI: 14.8%-21.2%) and 1.49 (CI:1.42-1.56), respectively. A polygenic risk score including the 122 variants produced an estimated area under the curve of 0.662 (0.752 including risk factors) among European ancestry individuals. Taken together, these findings substantially expand our knowledge of the genetic architecture of RCC providing avenues for functional investigation and risk prediction. Citation Format: Diptavo Dutta, Careen Foord, Mitchell J. Machiela, Mark P. Purdue, Stephen J. Chanock, The Renal Cancer Genetics Consortium. Multi-population GWAS meta-analysis identifies 86 susceptibility regions for renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB386.