Abstract 1292: Germline genetic, molecular and environmental factors modulate APOBEC mutagenesis in human tumors

Abstract

Abstract Background: Activity of APOBEC3 enzymes has been identified as a main source of somatic mutations of a specific type (C to T or G substitutions in the TCA or TCT motifs). This mutation pattern, known as the APOBEC signature, has been described in 16 of 30 tumor types explored by TCGA, with bladder cancer being one of top cancers enriched with APOBEC-signature mutations. Recently, we demonstrated that a risk allele of a bladder cancer GWAS SNP rs1014971 was significantly associated with increased APOBEC3B (A3B) mRNA expression and APOBEC mutagenesis in bladder tumors. Here, we aimed to further explore factors that can modulate APOBEC mutagenesis in human tumors. Methods: Isoform-specific expression analysis of all APOBEC3 genes (A3A, A3B, A3C, A3D, A3G, A3F, and A3H) was performed in TCGA datasets for seven tumor types enriched for APOBEC mutations (> 25% of the samples) - bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), cervical and endocervical cancers (CESC), head and neck squamous cell carcinoma (HNSC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and ovarian serous cystadenocarcinoma (OV). Expression and APOBEC mutagenesis pattern were analyzed by multivariate linear regression in relation to rs1014971 genotypes and adjusting for age, sex, race, DNA CpG methylation, copy number alterations (CNA), and human papilloma virus (HPV) infection status (where relevant). Survival analysis was performed using multivariate Cox regression models that included age, sex, tumor stage, rs1014971, and load of APOBEC mutations or mRNA expression of APOBEC3 splicing forms. Results: Analysis of APOBEC mutagenesis identified significant interplay between SNP rs1014971, expression of specific APOBEC3 splicing isoforms, and environmental factors (such as HPV infection). For example, SNP was important in BLCA and sub-types of HNSC, while HPV infection status was the main factor associated with APOBEC mutagenesis in CESC and HNSC. Importantly, variable contribution of mutagenic and non-mutagenic isoforms of A3A and A3B, which are generated by alternative splicing, emerged as significant factors contributing to APOBEC mutagenesis across human tumors. Survival of the cancer patients was also differentially influenced by these factors. Conclusions: These findings suggest that APOBEC mutagenesis pattern is tissue-specifically affected by germline genetic, molecular and environmental factors. Deeper understanding of these factors and their interplay may pave the way for preventive and treatment measures of human cancers towards precision medicine. Citation Format: A. Rouf Banday, Ariunaa Bayanjargal, Krizia-Ivana Udquim, Olusegun O Onabajo, Ludmila Prokunina-Olsson. Germline genetic, molecular and environmental factors modulate APOBEC mutagenesis in human tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1292. doi:10.1158/1538-7445.AM2017-1292