Abstract 151: Spatial patterns of APOBEC mutagenesis in the tumor microenvironment of Asian breast cancer

Abstract A common germline polymorphism in chromosome 22 involves the deletion of a large portion of the APOBEC3B gene that results in an APOBEC3A-B hybrid transcript. The hybrid transcript increases APOBEC3A activity and therefore increases APOBEC-associated mutagenesis, which is a common and important mutational signature in cancers. This deletion polymorphism is found with higher prevalence in Asians and is associated with increased risk of breast cancer in Asian women, as well as development of hypermutated cancers with greater immune cell infiltration. We used Stereo-seq spatial transcriptomics to study the relationship between APOBEC3B germline deletion, APOBEC mutagenesis, and the tumor immune microenvironment in Asian breast cancers with APOBEC3B germline deletion (carriers, either A3Bdel/del or A3Bdel/WT), and compared them to non-carriers. To study APOBEC mutagenesis, we constructed new bioinformatics pipelines to conduct variant calling and neoantigen prediction from Stereo-seq data whilst retaining spatial information. Unsupervised neighborhood clustering and cell type deconvolution revealed that the carriers have overall higher immune infiltration into the tumor compared to non-carriers. Somatic C>T mutations, the hallmark of APOBEC mutagenesis, were more prevalent in A3Bdel/del tumors. One sample showed a high overlap between somatic YTCA mutations, which are associated with APOBEC3A activity, and cancer associated fibroblasts (CAFs). Neoantigens originating from somatic mutations, specifically those arising from C>T mutations, were also more prevalent in A3Bdel/del tumors, but relatively few neoantigens arose from TCA or YTCA mutations. Our data suggest that biologically meaningful spatial resolution of APOBEC-associated somatic variants and neoantigens in tumor samples is possible using Stereo-seq technology. Citation Format: Zi Ching Tan, Yang Wu, Zhen Wei Neo, Mai Chan Lau, Siow Wee Chang, Joe Poh Sheng Yeong, Soo-Hwang Teo, Jia Wern Pan. Spatial patterns of APOBEC mutagenesis in the tumor microenvironment of Asian breast cancer [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 151.