Abstract 2486: APOBEC3B and APOBEC3C-H have opposite associations with DNA instability and immune cell infiltration in breast cancer tumors

Abstract

Abstract Introduction: APOBEC3 enzymes are strong mutagenic factors because of their cytidine deamination activity. In particular, the detrimentally of tumoral APOBEC3B (A3B) expression to clinical outcomes has been well established for breast cancer. We have previously demonstrated that high tumoral expression of many other APOBEC3s (A3C-H) confers better T cell anti-cancer immunity and survival benefit in breast cancer, an interesting finding given that these enzymes are DNA mutators. To this end, we hypothesized that each APOBEC3 has different activity on genomic instability and anti-cancer immunity in breast cancer tumors. Methods: Transcriptomic and clinical data for primary tumors were obtained from The Cancer Genome Atlas (TCGA). Patients were divided into thirds by gene expression and highest and lowest expressors were compared. Measurements of genomic or molecular features such as tumor mutation burden, neoantigen load, aneuploidy, homologous recombinant deficiency (HRD), intra-tumor heterogeneity (ITH), B and T cell receptor (BCR and TCR) diversity hypervariable complementarity- determining region 3 (CDR3) which are critical component of B cell immunoglobulin heavy chain were calculated using the datasets from previous publications. Results: As expected, tumor with high expression of A3B, DNA mutagenesis enzyme, were strongly associated with genome instability. Compared to tumors with low A3B expression, those with high expression had significantly greater mutation burden (1.9x for median value) and neoantigen load (1.8x), as well as scores for aneuploidy (1.7x), HRD (2.5x), and ITH (2.5x; all p values < 0.01).In contrast to A3B, we found that A3C, A3D, A3G and A3H are predominantly expressed in immune cells. Tumor with high expression of A3C demonstrated lower tumor mutation burden (0.9x) and aneuploidy (0.7x). Neoantigen load, HRD and ITH were significantly decreased (0.7 - 0.9x, all p< 0.001) in high A3D expressors. Although infiltrating leukocytes and their CD8 T cell subset were both decreased in tumors with high A3B expression, interestingly, they were increased 1.5-1.8-fold in tumors with high A3G or A3H expression. We also found that A3G and A3H expression had positive correlation with not only TCR diversity (2.0x and 2.1x for A3G and A3H respectively) and immune cytolytic activity (6.4x and 6.5x), but also both BCR diversity (2.6x and 2.1x) and number of unique CDR3s (6.4x and 4.8x) with all p < 0.001 significances. Conclusion: Our data suggests that APOBEC3B and APOBEC3C, 3D, 3G and 3H demonstrate opposite phenotype regarding DNA instability and immune cell infiltration in breast cancer. Citation Format: Mariko Asaoka, Santosh K. Patnaik, Takashi Ishikawa, Kazuaki Takabe. APOBEC3B and APOBEC3C-H have opposite associations with DNA instability and immune cell infiltration in breast cancer tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2486.