Identification of a tobacco-smoking induced mutation signature with biological and clinical significance in bladder cancer

Abstract Background: Tobacco-smoking is a known risk factor for bladder cancer (BCa). However, a typical tobacco-smoking induced mutation signature, COSMIC SBS4, established in lung and head-and-neck cancer, has not yet been virtually found in BCa. Methods: De novo mutation signature extraction was performed. Association of SBS4-like signature with tobacco-smoking and clinicopathologic and molecular features were analyzed with statistical and bioinformatics analysis. The role of AHR/CYP1A in BaP-induced carcinogenic effects was functionally investigated in RT4 and T24 cell lines. Results: We identified a mutation signature resembling the COSMIC SBS4 in a cohort of whole exome sequenced BCa tumors, with moderate contribution to the overall mutation load. Its relationship with tobacco-smoking was demonstrated given its transcriptional strand bias and association with tobacco-smoking history and other proven tobacco-induced mutation signatures, DBS2 and ID3. Load of this signature showed anti-correlation with APOBEC mutagenesis, enrichment in luminal unstable and depletion in stroma-rich molecular subtypes, and association with patients’ prognosis, tumor grade, tumor proliferation, immune infiltration, inflammation, IFN-response, and urothelial versus squamous differentiation. We computationally identified and functionally validated AHR/CYP1A axis as a pivot of tobacco-induced carcinogenesis in BCa. We proposed a hypothetic mechanistic model of tobacco toxicants-related BCa development and evolution in summary of the findings. Conclusions: A tobacco-smoking induced mutation signature with important biological and clinical significance is present in BCa. As a direct measurement of chronic tobacco genotoxic effects, it can be used for further investigations on BCa etiology and clinical management. AHR/CYP1A axis is essential in tobacco-induced carcinogenic process of BCa, which can be a potential target in BCa prevention and treatment.