Abstract 6621: Multi-modal profiling reveals the role of somatic structural variations in renal cell carcinoma

Abstract Renal cell carcinoma (RCC) is a heterogeneous malignancy with complex genetic underpinnings. While short-read sequencing has provided valuable insights into RCC genomics, the detection of large and complex structural variants (SVs) remains limited. In this study, we analyzed 17 pairs of RCC samples and identified 555 somatic SVs in RCC tumor samples using both long-read and short-read sequencing. All somatic SVs except repeat expansions are singleton variants, indicating high inter-tumor heterogeneity. Repeat expansions are recurrent, with the GAAGGG expansion in intron 7 of ARHGAP19 occurring with the highest prevalence of 64.29%. Next, to explore the potential impact of SVs on gene expression and chromatin accessibility, we generated snMultiome and bulk transcriptome data. We found that >25% SV-related genes exhibited significant changes in either gene expression or chromatin accessibility. The expression comparisons among mutant samples, non-mutant RCCs, and normal-adjacent kidneys identified putative protumor SVs (e.g. MET exon 14-15 duplication induced expression elevation in pRCC) and protective SVs (e.g. VCAN deletion induced expression loss in ccRCC). By integrating spatial transcriptome data, we investigated the spatial expression variations of SV-related genes and linked them to the clonal status of SVs. The most representative example is the differential MET expression observed in tumor cells within vascular cores and those lining the papillae membranes, suggesting the subclonal nature of MET duplication in pRCC. Finally, we constructed an RCC-specific pangenome to enhance SV calling and genotyping. Taken together, our results provide a comprehensive landscape of somatic SVs in RCC, shedding light on their effects on epigenomic and transcriptomic alterations. This study enhances our understanding of the role of SVs in RCC development and offers new insights into their potential clinical significance. Citation Format: Yuwei Zhang, Kapur Dhami, Yize Li, Cody Weimholt, Wagma Caravan, John Herndon, Reyka Jayasinghe, Song Cao, Melissa Reimers, Russell Pachynski, Feng Chen, Li Ding. Multi-modal profiling reveals the role of somatic structural variations in renal cell carcinoma [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 6621.