Abstract

Different sources of mutagenesis cause consistently identifiable patterns of mutations and mutational signatures that mirror the various carcinogenetic processes. We used publicly available data from the Cancer Genome Atlas to evaluate the associations between the activity of the mutational signatures and various survival endpoints in six types of urological cancers after adjusting for established prognostic factors. The predictive power of the signatures was evaluated with dynamic area under curve models. In addition, links between mutational signature activities and differences in gene expression patterns were analysed. APOBEC-related signature SBS2 was associated with improved overall survival (OS) and disease-specific survival (DSS) in bladder carcinomas in the multivariate analysis, while clock-like signature SBS1 predicted shortened DSS and progression-free interval (PFI) in clear cell renal cell carcinomas (ccRCC). In papillary renal cell carcinomas (pRCC), SBS45 was a predictor of improved outcomes, and APOBEC-related SBS13 was a predictor of worse outcomes. Gene expression analyses revealed various enriched pathways between the low- and high-signature groups. Interestingly, in both the ccRCC and pRCC cohorts, the genes of several members of the melanoma antigen (MAGE) family were highly upregulated in the signatures, which predicted poor outcomes, and downregulated in signatures, which were associated with improved survival. To summarize, SBS signatures provide substantial prognostic value compared with just the traditional prognostic factors in certain cancer types. APOBEC-related SBS2 and SBS13 seem to provide robust prognostic information for particular urological cancers, maybe driven by the expression of specific groups of genes, including the MAGE gene family.