Abstract 1018: Genetic landscape and functional exploration of kidney cancer predisposition in cross-ancestral populations

Abstract The genetic architecture of renal cell carcinoma (RCC) has not been fully characterized, particularly in Asian populations. Here, we conducted a genome-wide association study (GWAS) of 4, 692 RCC patients and 10, 116 controls of Chinese ancestry, extending to a multi-ancestry cohort totaling 879, 498 participants. Our approach unveiled 10 novel RCC-associated loci and a Chinese-specific locus at 12p13.33 with genome-wide significance. Utilizing GWAS results and cross-ancestry expression quantitative trait loci (eQTLs), we achieved a refined identification of RCC-related candidate causal variants and genes. These findings were substantiated through CRISPR-based screenings and multiplexed single-cell perturbations. Functionally, we established a novel association between rs28684409 and the oncogene RPL4 at the complex genetic locus 15q22.31. This top-down genetic study of RCC underscores the utility of integrating cross-ancestry GWASs, QTLs, and functional screens to deeply elucidate complex diseases and identify potential therapeutic targets. Citation Format: Hongji Dai, Xinlei Chu, Han Du, Shutong Yang, Yanxin Yao, Xinru Yu, Yanrui Zhao, Zhangyan Lyu, Wei Wang, Chao Sheng, Hong Zheng, Fangfang Song, Fengju Song, Mulin Jun Li, Kexin Chen. Genetic landscape and functional exploration of kidney cancer predisposition in cross-ancestral populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1018.