Abstract 969: Deciphering sex differences in clear cell renal cell carcinoma at the single-cell resolution

Abstract Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma, accounting for approximately 70% of cases. Strikingly, ccRCC exhibits a marked sex disparity in prevalence, being significantly more common in men than women. This disparity underscores the importance of systematically investigating sex differences to elucidate their implications for the diagnosis, prognosis, and therapeutic strategies of ccRCC. To address this, we generated a comprehensive single-nucleus sequencing atlas (snRNA-seq and snATAC-seq) comprising over 400, 000 nuclei from 65 ccRCC cases. This dataset was complemented by paired bulk proteogenomic data, enabling a multi-layered analysis of the molecular landscape. The study cohort, including 21 females and 44 males, reflects the sex distribution observed in ccRCC incidence within the general population. Our analysis uncovered sex-associated molecular differences in key pathways driving ccRCC progression. These include genes regulating the hypoxia-inducible factor (HIF) pathway, a hallmark of ccRCC, as well as lipid metabolism and energy homeostasis pathways, which are critical to ccRCC progression. Furthermore, genomic characterization revealed significant sex differences in tumor mutational burden (TMB) and specific genetic alterations, including higher mutation frequencies in KDM5C and MTOR in male tumors. These genetic differences were linked to distinct downstream effects, suggesting sex-specific impacts on tumor biology. These findings illuminate new opportunities for developing sex-informed therapeutic strategies and biomarkers, enabling a more precise and tailored approach to ccRCC screening and treatment. Citation Format: Xiangwei Fang, Yize Li, Xiyi Wei, Siqi Chen, Chia-Kuei Mo, Wagma Caravan, Preet Lal, Ruiyang Liu, Ilya Strunilin, Yizhe Song, Yuwei Zhang, Song Cao, Cody Weimholt, Feng Chen, Li Ding. Deciphering sex differences in clear cell renal cell carcinoma at the single-cell resolution [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 969.