APOBEC-Mediated Mutagenesis In Urothelial Carcinoma Is Associated With Improved Survival, Mutations In DNA Damage Response Genes, And Immune Response

Abstract

BackgroundThe 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. In this study, we explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival. We hypothesized that tumors with high levels of APOBEC-mediated mutagenesis would be enriched for mutations in DNA damage response genes and associated with higher expression of genes related to activation of the immune system.\n\nMethodsGene expression (n=408) and mutational (n=395) data from the Cancer Genome Atlas (TCGA) bladder urothelial carcinoma provisional dataset was utilized for analysis. Tumors were split into \"APOBEC-high\" and \"APOBEC-low\" tumors based on APOBEC enrichment score. Analysis was performed with R.\n\nFindingsPatients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs 18.5 months, p=0.005). Tumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2), and chromatin regulatory genes (MLL, MLL3), while APOBEC-low tumors are more likely to have mutations in FGFR3 and KRAS. APOBEC3A and APOBEC3B expression correlates with total mutational burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis and enrichment is associated with increased expression of immune-related genes, including interferon signaling.\n\nInterpretationTumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, potentially providing more single-strand DNA substrate for APOBEC3A and APOBEC3B, leading to a hypermutational phenotype and the subsequent immune response.\n\nHighlightsO_LIABPOEC enzymes, particularly APOBEC3A and APOBEC3B, are responsible for the predominant pattern of mutagenesis in bladder cancer\nC_LIO_LITumors enriched for APOBEC-mediated mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, while tumors not enriched for APOBEC-mediated mutagenesis are more likely to have mutations in KRAS and FGFR3\nC_LIO_LIAPOBEC enrichment is associated with upregulation of genes involved in the immune response\nC_LI