The Study of the Environmental Etiologies of Urothelial Bladder Cancers through Mutational Analysis

Cancer is a disease caused and manifested by somatic mutations, which arise from multiple mutational processes such as aging, smoking, UV radiation, and carcinogen exposure. Recent studies have identified 30 distinct somatic mutational signatures across tumors; this signature catalogue can be used as a reference to explore the etiology behind different cancer types. APOBEC3-mediated DNA deamination is a mutagenic process that generates unique mutational footprints. APOBEC3 enzymes have multiple functions due to their cytidine deaminating activity, including the role of mediating viral immunity. In the context of viral infection, APOBEC3s deaminate and mutate viral nucleic acids, leading to viral restriction. In addition to editing viral genomes, upregulation of APOBEC3s can also lead to mutagenesis of the host genome and thus may drive tumorigenesis. The mutational signatures attributed to APOBEC3 activity are major somatic signatures in several cancer types, including bladder cancers. In these tumors, there is a strong correlation between tumor expression of two APOBEC3 genes (APOBEC3A or APOBEC3B) and enrichment of the APOBEC mutational signature. However, no correlation between host APOBEC mutagenesis and viral factors has been shown in bladder tissue. The leading cause of bladder cancer is smoking; yet, the smoking mutational signature is not observed in bladder cancer. Both environmental factors and host genetics modulate bladder cancer risk. Cigarettes, arsenic, and aromatic amines have been found to increase bladder cancer risk. Environmental carcinogens which cause DNA damage may induce inflammation and stimulate the APOBEC response. APOBEC3A and APOBEC3B expression can be induced by DNA damage in vitro in bladder. Inflammation, a result of interferon signaling, may be a common theme to induction of APOBEC mutagenesis. In this thesis, I present an investigation into the relationships between environmental factors and somatic processes in bladder tissues. The major risk factor of bladder cancer, cigarette smoking, was found to positively correlate with an increase of a mutational signature, Signature 5. Additionally, the APOBEC signatures were found to be enriched in non-smokers and former smokers. Further analysis finds that molecular evidence of BK polyomavirus in bladder tumors is associated with the presence of APOBEC-type driver mutations in non-muscle invasive bladder cancer