Zhang Jianhui, Schulz Wolfgang A, Li Yan, Wang Rui, Zotz Rainer, Wen Denggui, Siegel David, Ross David, Gabbert Helmut E, Sarbia Mario
Institute of Pathology, University of Duesseldorf, Moorenstr. 5, Germany.
Carcinogenesis. 2003 May;24(5):905-9. doi: 10.1093/carcin/bgg019.
NAD(P)H: quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme, important in the detoxification of environmental carcinogens. A single base substitution (C --> T) polymorphism at nucleotide 609 (null-allele) of NQO1 gene impairs stability and function of the NQO1 protein. To investigate the association of this NQO1 polymorphism with susceptibility to esophageal squamous cell carcinoma (ESCC), the NQO1 C609T genotypes were determined by PCR-RFLP analysis in 450 patients with ESCC (257 German Caucasians and 193 northern Chinese) and 393 unrelated healthy controls (252 German Caucasians and 141 northern Chinese). Additionally, NQO1 protein expression was determined by immunohistochemistry in a subset of 74 ESCC (50 German, 24 Chinese). A significant difference in NQO1 C609T genotype distribution was observed between Caucasian healthy controls (C/C, 73.4%; C/T, 25.0%; T/T, 1.6%) and Chinese healthy controls (C/C, 34.0%; C/T, 49.7%; T/T, 16.3%) (chi(2) = 68.40, P < 0.001). The NQO1 T/T genotype significantly increased the risk for developing ESCC in both Caucasian subjects (OR = 4.62, 95% CI = 1.54-13.86) and Chinese subjects (OR = 1.81, 95% CI = 1.04-3.15), compared with the combined C/C and C/T genotypes. In Chinese subjects, this increased susceptibility was pronounced in patients with family history of upper gastrointestinal cancers (OR = 2.18, 95% CI = 1.14-4.17). Immunohistochemical analysis showed NQO1 protein expression in 53 carcinomas, whereas 21 carcinomas were negative. Negativity for NQO1 expression correlated strongly with the NQO1 genotype, being present in 8.6% of cases with C/C, 22.2% of cases with C/T and 100% of cases with T/T genotype (chi(2) = 16.60, P < 0.001). In summary, the association of the NQO1 C609T polymorphism with ESCC in genetically distinct populations makes a strong argument for its importance in carcinogenesis of ESCC in the German Caucasian and the northern Chinese population.
烟酰胺腺嘌呤二核苷酸磷酸（NAD(P)H）：醌氧化还原酶1（NQO1）是一种抗氧化酶，在环境致癌物解毒过程中起重要作用。NQO1基因第609位核苷酸处的单碱基替换（C→T）多态性（无效等位基因）会损害NQO1蛋白的稳定性和功能。为了研究这种NQO1多态性与食管鳞状细胞癌（ESCC）易感性的关系，通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）分析，对450例ESCC患者（257名德国白种人和193名中国北方人）及393名无血缘关系的健康对照者（252名德国白种人和141名中国北方人）进行了NQO1 C609T基因型测定。此外，采用免疫组织化学方法对74例ESCC患者（50名德国人、24名中国人）的一个亚组进行了NQO1蛋白表达测定。在白种人健康对照者（C/C，73.4%；C/T，25.0%；T/T，1.6%）和中国健康对照者（C/C，34.0%；C/T，49.7%；T/T，16.3%）之间观察到NQO1 C609T基因型分布存在显著差异（χ² = 68.40，P < 0.001）。与C/C和C/T基因型组合相比，NQO1 T/T基因型显著增加了白种人（比值比[OR] = 4.62，95%可信区间[CI] = 1.54 - 13.86）和中国人（OR = 1.81，95% CI = 1.04 - 3.15）患ESCC的风险。在中国人群中，这种易感性增加在有上消化道癌家族史的患者中更为明显（OR = 2.18，95% CI = 1.14 - 4.17）。免疫组织化学分析显示，53例癌组织中有NQO1蛋白表达，而21例癌组织为阴性。NQO1表达阴性与NQO1基因型密切相关，在C/C基因型病例中占8.6%，C/T基因型病例中占22.2%，T/T基因型病例中占100%（χ² = 16.60，P < 0.001）。总之，NQO1 C609T多态性在遗传背景不同的人群中与ESCC的关联有力地证明了其在德国白种人和中国北方人群ESCC致癌过程中的重要性。
