Allelic variants in xenobiotic metabolism genes predict susceptibility and worse prognosis of urothelial bladder cancer

Abstract

Biomarkers that identify tumors with better/worse prognosis can help reduce treatment costs and contribute to patient survival. In urothelial bladder cancer (UBC), accurate prediction of recurrence and progression is essential to inform therapeutic management. Herein, we explore the role of genetic variants of xenobiotic metabolic pathways in UBC susceptibility and prognosis. In total, 295 participants with UBC and 295 controls were genotyped using TaqMan® probes. CYP1A1 (rs1048943), CYP3A4 (rs4646437), CYP3A5 (rs4646450), UGT2B7 (rs7438135), and UGT2B15 (rs3100) allele frequencies were compared between UBC patients and controls and were analyzed concerning tumor grade, invasion, and recurrence. CYP3A4 (AA) increased susceptibility to UBC 3-fold when interacting with CYP3A5 (AA+AA). The susceptibility was higher in CYP3A4 (AA) males (OR=3.189) and individuals exposed to pesticides (OR=5.492). When interacting with hypertension, the allele C of CYP1A1 also increased UBC susceptibility by 2-fold. The UGT2B15 mutant allele was associated with high-grade tumors (OR=2.196) and recurrences (OR=2.561), as well as tumor grade when associated with mutated alleles of CYP3A4 (OR=6.171) and CYP3A5 (OR=3.492). Genes-encoding proteins were further analyzed using the STRING program, demonstrating that the proteins had known interactions in databases and were co-expressed. This study is a pioneer in evaluating these variants in a Latin American population from Brazil and confirms occupational pesticide exposure as a risk factor for UBC, mainly in genetically susceptible individuals. Furthermore, these variants may have additional clinical value for predicting susceptibility and prognostic stratification in patients with exposure-related cancers such as UBC.