Abstract 389: Integrative genomic analyses of mutation signatures, immunogenicity and germline copy number variation of the APOBEC genes in multiple cancer types

Abstract

Abstract The APOBEC-signature mutation has been frequently observed in multiple cancer types, including bladder, breast, and lung adenocarcinoma. Increased expression of the APOBEC3A and APOBEC3B genes is known to induce APOBEC-signature mutations in these cancer types. Limited studies have investigated whether the mutation patterns are associated with individual isoforms of the APOBEC3A and APOBEC3B genes, particularly the isoform uc011aoc from an APOBEC3A/3B chimera that is primarily generated by a common germline deletion. Previous studies have shown that somatic missense mutations contribute to neoantigen load and consequently may affect cancer immunogenic abilities such as attracting tumor infiltration lymphocytes (TILs). However, the influence of APOBEC-signature mutations on tumor immunology remains largely unknown. In this study, we systematically analyzed the APOBEC isoform expression and mutation signature, neoantigen load, and copy number variations in ~4000 tumor samples across 10 cancer types using data from The Cancer Genome Atlas. Using multiple regression analyses that included all isoforms of both APOBEC3A and APOBEC3B, we found that the isoforms uc003awn (APOBEC3A) and uc011awo (APOBEC3B) were significantly associated with APOBEC-signature mutations (defined as TCW change to either TTW or TGW mutations) in multiple cancer types, while the association for uc011aoc was observed only in breast cancer. We also observed that APOBEC-signature mutations were positively associated with neoantigen load in all cancer types except lung adenocarcinoma and kidney carcinoma (P < 0.05). To further investigate the effects of these mutations on TILs, we used gene expression data and the tool CIBERSORT to predict the relative compositions of immune cells for each cancer type. We found that APOBEC-signature mutations were significantly associated with the compositions of CD8+ and CD4 memory-activated T cells only in breast and bladder cancer types. Furthermore, we found that neoantigen load was significantly associated with these cell compositions in multiple cancer types, but was not observed in breast cancer. Lastly, our results showed that a germline common deletion in APOBEC3A/B was associated with a significantly increased expression level of uc011aoc isoform, but decreased expression levels of both uc003awn and uc011awo across cancer types. In addition, we found that the deletion was associated with the evaluated neoantigen load and the composition of T cells (CD8+) in breast cancer. The results suggest potential mechanisms for the association of APOBEC3A/B gene deletion with increased breast cancer risk reported from previous genome wide association studies. Our study provides novel insights into understanding the biological and immunological mechanisms through which APOBEC genes may be involved in carcinogenesis. Citation Format: Xingyi Guo, Xiao-ou Shu, Jiandong Bao, Wanqing Wen, Qiuyin Cai, Jirong Long, Wei Zheng. Integrative genomic analyses of mutation signatures, immunogenicity and germline copy number variation of the APOBEC genes in multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 389.