Abstract 2385: Discovery of non-coding somatic driver mutations in single-cell chromatin accessibility data

Abstract scATAC-seq data presents unprecedented opportunities to identify somatic mutations in regulatory regions. However, existing tools struggle to reliably detect somatic mutations from scATAC-seq data due to the unbalanced coverage between tumor and normal cells. To address this, we developed scVar, a pipeline designed to detect somatic mutations from scATAC-seq data. Applying scVar to snATAC-Seq data from about 200 tumor samples spanning 10 cancer types, we identified over 70, 000 somatic mutations, with 95% located in non-coding regions. Comparison with bulk WGS and WXS data demonstrated that scVar achieves high accuracy in detecting somatic mutations. Notably, scVar effectively recaptured the UV mutational signature in skin cancer. Variant allele frequency (VAF) analysis revealed an increase in VAF in snATAC-seq data compared to WXS data. For tumor suppressor genes such as TP53, VHL, BAP1, CDH1, CBFB, TGIF1, and ZNF750, homozygous mutations with VAFs approaching 1 were consistently detected in snATAC-seq data, emphasizing the critical role of biallelic variants in tumor initiation. We also observed recurrent TERT promoter mutations across 20 samples, with VAFs close to 1, which were associated with increased chromatin accessibility and expression in glioblastoma, but not in skin cancer. Additionally, novel promoter mutations, such as in CDK12, were linked to increased gene expression. These findings highlight the utility of scVar in uncovering somatic mutations and their functional effects in non-coding regions from scATAC-seq data. Citation Format: Song Cao, Liting Zhang, Alla Karpova, Fernanda M. Rodrigues, Yingduo Song, Nadezhda V. Terekhanova, Benjamin J. Raphael, Ryan C. Fields, Feng Chen, Li Ding. Discovery of non-coding somatic driver mutations in single-cell chromatin accessibility data [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 2385.