Abstract 3416: APOBEC3C-H gene expression and APOBEC3-mediated RNA editing in breast cancer tumors are associated with immune response and improved outcome
Authors: Asaoka Mariko , Patnaik Santosh K. , Katsuta Eriko , Ishikawa Takashi , Takabe Kazuaki 
Published: August 2019

Abstract
APOBEC enzymes are strong mutagens in breast cancer. High APOBEC3B (A3B) expression in tumors is associated with poor prognosis, but clinical significance of the other APOBEC3s (A3A, C-H) is unclear. We investigated the associations of A3A and C-H with survival and tumor immune activity in 1091 primary breast cancer tumors of The Cancer Genome Atlas project. Tumor cytolytic activity, T cell receptor (TCR) diversity, and immune cell fractions were estimated from RNA sequencing data. Patients were divided into 3 equal groups by gene expression to compare high and low expressors. Cox, Spearman and t tests were used for survival, correlation and comparison analyses, respectively. Hallmark gene-sets were used for enrichment analysis. RNA editing was determined from whole exome and RNA sequencing data for 5,208 sites of 3,630 gene transcripts that are known to undergo APOBEC3-mediated RNA editing. Examination of 55 breast cancer cell-lines of Cancer Cell Line Encyclopedia showed that A3B and A3C represented 91% of A3 gene expression. Examination of Illumina Human Body Map showed that all APOBEC3s are expressed in leukocytes at a 4-450x higher level compared to breast. In patients, expression of A3B but not other APOBEC3s was higher in tumors compared to normal tissue (4.5x). A3C-H expression levels correlated positively with both leukocyte and lymphocyte fractions in tumor (r = 0.29-0.70 and 0.20-0.50, resp.). Expression of genes related to immune function like interferon response and complement activation was enriched in high A3C-H expressors, which also had significantly more CD4 and CD8 T cells, and TCR diversity (2.3-4.0x, 2.1-5.4x and 1.3-2.1x, resp.). Concordantly, for each of A3C-H, expression correlated with tumor immune cytolytic activity (r = 0.31-0.79), which was increased 3.1-7.9x in high expressors. A3B or A3A gene expression levels had no effect on overall survival (OS), but higher expression for each of A3C-H was significantly associated with improved OS (HR = 0.45-0.66). To obtain insights on any causative mechanism for the prognostic value of A3C-H expression, we examined APOBEC3-mediated C&gt;U RNA editing in the tumors. RNA editing at a mean level of 6.3% (SD = 4.3%) was observed among tumors for 767 genes. Editing was not associated with tumor subtype or pathologic stage but tumors with high editing had 1.4-11x higher gene expression of A3A and C-H (P &lt;0.05 for all). TCR diversity and immune cytolytic activity in tumors correlated with RNA editing (P &lt;0.001 for both), and increased editing was associated with improved disease-free interval (P &lt;0.05). Even though APOBEC3C-H are DNA mutators, their high expression in tumor is associated with a strong immune response and improved survival in breast cancer. This is also observed for APOBEC3-mediated RNA editing, suggesting that RNA editing of specific genes by APOBEC3s may be promoting immune activity against cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Mariko Asaoka, Santosh K. Patnaik, Eriko Katsuta, Takashi Ishikawa, Kazuaki Takabe. APOBEC3C-H gene expression and APOBEC3-mediated RNA editing in breast cancer tumors are associated with immune response and improved outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3416.