Abstract 3733: Disconnect between APOBEC3 expressions and mutations across cancers

Abstract

DNA of many tumors is barraged by C-to-T/G mutations within TCW (W:T,A). These mutations are attributed to the aberrant expression and activity of APOBEC3 enzymes. They have been shown to account for many driver mutations in genes such as PIK3CA, ERBB2, and PPP2R1A, however their precise source and also their roles in tumor development, evolution, and patient survival are debated. Currently, quantification of APOBEC3 expression changes in tumor cells is confounded by the ubiquitous expression of these enzymes in infiltrating immune cells. In this study, we used quantitative biology approaches to separate the expression profiles of APOBEC3 enzymes in tumor and tumor microenvironment cells and determine their associations with tumor mutational signatures. For this purpose, we analyzed diverse datasets including TCGA tumor/matched normal RNAseqs, tumor somatic mutations, cell line RNAseqs and mutations, estimates of tumor purities and immune cell compositions, and expression of purified cell populations to precisely determine how APOBEC3 enzymes are dysregulated across tumors and whether their dysregulations are proportional to tumor mutational signatures. Unexpectedly, we found that dysregulation of APOBEC3 enzymes is independent of tumor C-to-T/G mutational burden. Importantly, our data suggest that this disconnect is likely not due to the episodic bursts of APOBEC3-induced mutations in cancer. Citation Format: Azad Khosh, Hamid Hamidi, Hamzeh Rahimi, Diako Ebrahimi. Disconnect between APOBEC3 expressions and mutations across cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3733.