Login to Access Video or Poster Abstract: MP44-12
Sources of Funding: This research was supported in part by the John P. Hanson Foundation for Cancer and Cellular Research. The results shown here are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/

Introduction

The APOBEC family of enzymes is responsible for a mutation signature characterized by a TcW->T/G mutation. APOBEC-mediated mutagenesis is implicated in a wide variety of tumors, including bladder cancer. However, less is known about regulation and function of the APOBEC genes and their subsequent mutation signature. In this study, we explore the APOBEC mutational signature in bladder cancer and the relationship with mutation burden, molecular classification, gene expression, and survival.

Methods

The Cancer Genome Atlas (TCGA) bladder urothelial carcinoma data was downloaded from cBioPortal (http://cbioportal.org) and the Broad Institute (http://gdac.broadinstitute.org). APOBEC enrichment score was calculated as previously described (Nat Genet 2013;45:970). Tumors with >2-fold enrichment with a Benjamini-Hochberg corrected p-value <0.05 were considered high in APOBEC enrichment. Statistical analysis was performed with R. Functional annotations were performed with DAVID (http://david.ncifcrf.gov).

Results

Expression of APOBEC3A and APOBEC3B are associated with the mutational burden in bladder cancer (r=0.18, p<0.001; r=0.334, p<0.001). High APOBEC enrichment score is associated with improved overall survival (Figure 1A). APOBEC enrichment does not vary between TCGA molecular subtypes 1-4 (Figure 1B). Of the top mutated genes in bladder cancer, patients with high APOBEC enrichment are more likely to have mutations in TP53, ERBB2, KMT2C and PIK3CA, but not ARID1A, CSMD3, RB1, KMT2D, KDM6A, or STAG2. Genes with expression positively associated with APOBEC enrichment (including PD-1, CTLA-4, TIM-3, and TIGIT) are involved in IFN-gamma signaling, antigen processing and presentation, and regulation of the immune response, while genes negatively associated with APOBEC enrichment are involved in translational initiation and ribosome assembly.

Conclusions

APOBEC enzymes are a major source of mutation in bladder cancer. Both luminal and basal subtypes of bladder cancer have similar APOBEC mutational signatures. This signature is associated with overall survival as well as expression of immune-related genes. Further study of regulation of APOBEC enzymes may provide further insight into the mutational landscape and potential therapeutics for bladder cancer.

Funding

This research was supported in part by the John P. Hanson Foundation for Cancer and Cellular Research. The results shown here are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/