Functional POR A503V is associated with the risk of bladder cancer in a Chinese population

• Published in: Scientific reports Vol. 5; no. 1; p. 11751
• Main Authors: Xiao, Xue, Ma, Gaoxiang, Li, Shushu, Wang, Meilin, Liu, Nian, Ma, Lan, Zhang, Zhan, Chu, Haiyan, Zhang, Zhengdong, Wang, Shou-Lin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.06.2015; Nature Publishing Group
• Subjects: 38/23; 38/70; 692/53/2423; 692/699/67/589/1336; 82/80; Aged; Animals; Bladder cancer; Cancer; Carcinogens; Case-Control Studies; China; CHO Cells; Colonies; Cricetinae; Cricetulus; Cytochrome; Cytochrome c; Cytochrome P-450 Enzyme System - genetics; Cytochrome P450; Exons; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Geriatrics; Health risk assessment; Hormones; Humanities and Social Sciences; Humans; Invasiveness; Male; Middle Aged; Mitomycin C; multidisciplinary; Mutation, Missense; Oxidoreductase; Polymorphism, Single Nucleotide; Protective Factors; Risk Factors; Science; Sequence Analysis, DNA; Smoking; Urinary bladder; Urinary Bladder Neoplasms - genetics; China
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep11751

Human cytochrome P450 oxidoreductase (POR) plays important roles in the metabolism of exogenous carcinogens and endogenous sterol hormones. However, few studies have explored the association between POR variants and the risk of bladder cancer. In this study, we first sequenced all 16 POR exons among 50 randomly selected controls and found three variants, rs1135612, rs1057868 (A503V) and rs2228104, which were then assessed the relation to risk of bladder cancer in a case-control study of 1,050 bladder cancer cases and 1,404 cancer-free controls in a Chinese population. People with A503V TT genotype have a decreased risk of bladder cancer in a recessive model (TT vs . CC/CT, OR = 0.73, 95% CI = 0.57–0.93), which was more pronounced among elderly male, non-smoking, subjects. Especially, A503V TT genotype showed a protective effect in the invasive tumor stage. Functional analysis revealed that A503V activity decreased in cytochrome c reduction (50.5 units/mg vs . 135.4 units/mg), mitomycin C clearance (38.3% vs . 96.8%) and mitomycin C-induced colony formation (78.0 vs 34.3 colonies per dish). The results suggested that POR A503V might decrease the risk of bladder cancer by reducing its metabolic activity and should be a potential biomarker for predicting the susceptibility to human bladder cancer.