Abstract : Differential Network Analysis Reveals Pathways Associated with APOBEC3 Mutational Signature in Breast Cancer

Abstract The human genome encodes seven APOBEC3 enzymes (A3A/B/C/D/F/G/H) known for their ability to mutate DNA. These enzymes primarily function to restrict viral infections by introducing C-to-U mutations in viral genomes. However, certain A3 family members, particularly A3A and A3B, can also mutate cellular DNA, contributing to tumor initiation and progression. Several cancers including breast, bladder, cervical, head and neck, and skin exhibit characteristic C-to-T mutations (SBS2 and SBS13) associated with aberrant A3 enzyme expression or activity. While SBS2 and SBS13 mutational signatures are generally more prevalent in cancers with elevated A3A and A3B transcript levels, this correlation does not consistently hold at the individual TCGA donor level. Many donors exhibit high SBS2/13 levels despite little or no A3A/B mRNA expression, and vice versa. This discrepancy is thought to arise from varying levels of DNA repair among donors and/or the episodic nature of A3 dysregulation. Here, we propose and test a third hypothesis: that changes in the interaction networks of A3 enzymes, rather than their expression levels alone, underlie SBS2/13 mutational signatures. Specifically, we hypothesize that the A3 interactome determines whether tumors undergo A3-induced tumorigenesis in a donor-specific manner. To investigate this, we analyzed 1,082 TCGA breast tumors, grouping them into high and low SBS2/13 categories. Using Parsimonious Gene Correlation Network Analysis (PGCNA), we constructed gene expression networks for each group and performed a differential network analysis. Preliminary findings reveal significant differences between the networks, particularly involving genes such as GATA3, CDH1, and PIK3CA. Our ongoing work aims to extend this analysis across all TCGA tumors to fully explore gene network changes associated with A3 mutational signatures. Citation Format: Mohadeseh Soleimanpour, Diako Ebrahimi. Differential Network Analysis Reveals Pathways Associated with APOBEC3 Mutational Signature in Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-06-21.