Hung Rayjean J, Boffetta Paolo, Brennan Paul, Malaveille Christian, Gelatti Umberto, Placidi Donatella, Carta Angela, Hautefeuille Agnès, Porru Stefano
International Agency of Research on Cancer, Lyon 69008, France.
Carcinogenesis. 2004 Jun;25(6):973-8. doi: 10.1093/carcin/bgh080. Epub 2004 Jan 16.
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.
吸烟和职业暴露是膀胱癌的主要危险因素，这是通过接触多环芳烃（PAHs）和芳香胺实现的，这些物质会导致氧化应激和DNA损伤。在人类中，几种在氧化应激中起关键作用的酶具有多态性。髓过氧化物酶（MPO）产生一种用于杀菌活性的强氧化剂，并激活烟草烟雾中的致癌物。儿茶酚-O-甲基转移酶（COMT）催化内源性和外源性物质的甲基化，并防止氧化还原循环。NAD（P）H：醌氧化还原酶（NQO1）催化醌类化合物的双电子还原，这也能保护细胞免受氧化还原循环的影响。锰超氧化物歧化酶（MnSOD）保护细胞免受自由基损伤。为了验证膀胱癌风险可能受到调节氧化应激的基因多态性影响的假设，特别是通过与环境致癌物相互作用，我们在意大利北部布雷西亚的男性中进行了一项基于医院的病例对照研究。我们在1997年至2000年期间招募并访谈了201例新发病例和214名对照。职业医生对PAHs和芳香胺的职业暴露进行了盲法编码。应用无条件多变量逻辑回归来模拟基因多态性与膀胱癌风险之间的关联，并评估吸烟和职业暴露改变的影响。MPO G-463A纯合变异与膀胱癌风险降低相关，OR为0.31（95%CI = 0.12 - 0.80）。MnSOD Val/Val基因型增加了膀胱癌风险，OR为1.91（95%CI = 1.20 - 3.04），并且与吸烟（OR = 7.20，95%CI = 3.23 - 16.1）和PAH（OR = 3.02，95%CI = 1.35 - 6.74）存在联合效应。我们未观察到COMT Val108Met多态性的影响。这些发现表明，膀胱癌的个体易感性可能受MPO和MnSOD多态性调节，并且参与氧化应激反应的遗传因素与环境致癌物的组合可能在膀胱癌发生中起重要作用。
