Genetic polymorphisms of MPO, COMT, MnSOD, NQO1, interactions with environmental exposures and bladder cancer risk

Abstract

Tobacco smoking and occupational exposure are major risk factors of bladder cancer via exposure to polycyclic aromatic hydrocarbons (PAHs) and aromatic amines, which lead to oxidative stress and DNA damage. Several enzymes, which play key roles in oxidative stress are polymorphic in humans. Myeloperoxidase (MPO) produces a strong oxidant for microbicidal activity, and activates carcinogens in tobacco smoke. Catechol-O-methyltransferase (COMT) catalyzes the methylation of endo- and xenobiotics and prevents redox cycling. NAD(P)H:quinone oxidoreductase (NQO1) catalyzes the two-electron reduction of quinoid compounds, which also protects cells from redox cycling. Manganese superoxide dismutase (MnSOD) protects cells from free radical injury. To test the hypothesis that the risk of bladder cancer can be influenced by polymorphisms in the genes that modulate oxidative stress, in particular by interacting with environmental carcinogens, we conducted a hospital-based case-control study among men in Brescia, Northern Italy. We recruited and interviewed 201 incident cases and 214 controls from 1997 to 2000. Occupational exposures to PAHs and aromatic amines were coded blindly by occupational physicians. Unconditional multivariate logistic regression was applied to model the association between genetic polymorphisms and bladder cancer risk and the effect of modifications of smoking and occupational exposures were evaluated. MPO G-463A homozygous variant was associated with a reduced risk of bladder cancer with an OR of 0.31 (95% CI = 0.12-0.80). MnSOD Val/Val genotype increased the risk of bladder cancer with OR of 1.91 (95% CI = 1.20-3.04), and there was a combined effect with smoking (OR = 7.20, 95% CI = 3.23-16.1) and PAH (OR = 3.02, 95% CI = 1.35-6.74). We did not observe an effect of COMT Val108Met polymorphism. These findings suggest that individual susceptibility of bladder cancer may be modulated by MPO and MnSOD polymorphisms, and that the combination of genetic factors involved in oxidative stress response with environmental carcinogens may play an important role in bladder carcinogenesis.

NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Pro187Ser Polymorphism and the Risk of Lung, Bladder, and Colorectal Cancers: a Meta-analysis

“…We identified nine studies examining the effect of the NQO1 Pro187Ser polymorphism on the risk of bladder cancer (46)(47)(48)(49)(50)(51)(52)(53)(54); one study (51) was excluded due to the lack of genotype information. The remaining eight studies included a total of 1,410 cases and 1,485 controls.…”

The NQO1 rs1800566 Polymorphism and Risk of Bladder Cancer: Evidence from 6,169 Subjects

“…After further retrieved, 12 articles were excluded because of the following reasons: three were for review or meta-analysis articles (Gonzalez, 1997;Chao et al, 2006;Ersoy Tunali et al, 2011); one did not focus on the NQO1 rs1800566 polymorphism but on NQO2 (exon 3, T14055C) polymorphism (Wen et al, 2009); two were for the correlation between the NQO1 rs1800566 polymorphism and NQO1 activity (Basu et al, 2004;Jamieson et al, 2007); two were for the correlation between the NQO1 rs1800566 polymorphism and p53 mutations (Martone et al, 2000;Ryk et al, 2006); one was for the correlation between the NQO1 rs1800566 polymorphism and clinical course of bladder cancer (Sanyal et al, 2007); Three studies did not report gene frequencies (Vineis et al, 2007;Dhaini et al, 2012;Ersoy Tunali et al, 2012). Therefore, 12 studies (Schulz et al, 1997;Choi et al, 2003;Park et al, 2003;Hung et al, 2004;Moore et al, 2004;Sanyal et al, 2004;Broberg et al, 2005;Terry et al, 2005;Figueroa et al, 2008;Wang et al, 2008;Paonessa et al, 2009;Pandith et al, 2011) were included in our meta-analysis. The detailed characteristics of the included studies were shown in Table 2.…”

Different Association of Manganese Superoxide Dismutase Gene Polymorphisms with Risk of Prostate, Esophageal, and Lung Cancers: Evidence from a Meta-analysis of 20,025 Subjects

“…The inefficient MnSOD protein in the mitochondria may leave the cell vulnerable to oxidative damage without its full defense against superoxide radicals, which leads to protein oxidation and DNA mutations (Ambrosone et al, 1999). The Ala variant of the MnSOD protein has been reported to increase risk of several types of malignancies, such as breast cancer (Mitrunen et al, 2001), prostate cancer (Choi et al, 2008), esophageal cancer (Murphy et al, 2007), and cervical cancer (Tong et al 2009), and additional studies showed that it is likely to be associated with alteration of ROS and thus predisposed to a lower risk of liver (Sutton et al, 2003), lung (Wang et al, 2001), and bladder (Hung et al, 2004) cancers. The discrepancy may be partially due to minor effect of this gene polymorphism on cancer risk, or the small sample size reported in each study.…”