Abstract PD8-11: APOBEC3 contributes to mutational load in breast cancer

Breast cancer results in large part from the accumulation of multiple mutations in premalignant cells, which provide a molecular basis for genetic diversity. This genetic diversity in premalignant cells allows selection for increased proliferation and survival and ultimately leads to invasion, metastasis, and therapeutic resistance. Recent genome-wide sequencing data showed that APOBEC3B (A3B) contributes to mutational load in breast cancer. A3B, a DNA cytosine deaminase, is overexpressed in more than 50% of breast tumors and more than 75% of breast cancer cell lines. Its overexpression and aberrant activation lead to unexpected clusters of mutations in the majority of breast cancers. This phenomenon of clustered mutations, termed kataegis ( shower in Greek) forms a unique mutation signature in breast cancer. On the basis of the finding that A3B is a key molecular determinant of the mutator phenotype in breast cancer, the goal of our research is to utilize informatics tools to systematically characterize genetic alterations of APOBEC3 family proteins in breast cancer genomic data and define the molecular impact of altered APOBEC3 family proteins on mutability and anti-tumor immunity. Our data showed that the mutation rate and copy number amplification/deletion of APOBEC3 genes are low. The levels of APOBEC3A (A3A) and A3B are highly correlated and are highest in Basal subtype and lowest in Luminal A tumors, in concordance with the proliferation of subtypes. Additionally, A3A and A3B are significantly correlated with total mutational load as well as with TP53 mutation, and with somatic copy number alterations (SCNA), especially focal SCNA. Among APOBEC3 genes, A3B is significantly associated DNA replication, DNA damage repair, cell cycle and proteasome signatures, and shows predictive and prognostic capacity in ER-positive patients. Interestingly, A3G expression is strongly associated with immune response signature genes in all breast tumors. Consequently, A3G is highly associated with tumor-infiltrating lymphocytes in breast and several other disease types. In summary, our data demonstrate distinct expression pattern of APOBEC3 genes in different breast cancer subpopulations. Overexpression of different APOBEC3 family members leads to distinct molecular consequences. These data provide new molecular insights into pathophysiological functions of APOBEC3 genes in breast cancer and provide therapeutic opportunities for the breast cancer patients whose tumors have altered APOBEC3 expression levels and potentially are driven by APOBEC3 genes. Importantly, APOBEC3G is associated with evidence of immune activation that may signal responsiveness to immune checkpoint inhibitors. Citation Format: Zhao W, Peng Y, Mills GB, Peng G. APOBEC3 contributes to mutational load in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD8-11.