Abstract
BackgroundThe functional polymorphism (rs1800566) in the NQO1 gene, a 609C>T substitution, leading to proline-to-serine amino-acid and enzyme activity changes, has been implicated in cancer risk, but individually published studies showed inconclusive results.Methodology/Principal FindingsWe performed a meta-analysis of 20 publications with a total of 5,491 cases and 5,917 controls, mainly on gastrointestinal (GI) cancers. We summarized the data on the association between the NQO1 609C>T polymorphism and risk of GI cancers and performed subgroup analyses by ethnicity, cancer site, and study quality. We found that the variant CT heterozygous and CT/TT genotypes of the NQO1 609 C>T polymorphism were associated with a modestly increased risk of GI cancers (CT vs. CC: OR = 1.10, 95% CI = 1.01 – 1.19, P heterogeneity = 0.27, I 2 = 0.15; CT/TT vs. CC: OR = 1.11, 95%CI = 1.02 – 1.20, P heterogeneity = 0.14; I 2 = 0.27). Following further stratified analyses, the increased risk was only observed in subgroups of Caucasians, colorectal cancer in Caucasians, and high quality studies.ConclusionsThis meta-analysis suggests that the NQO1 609T allele is a low-penetrance risk factor for GI cancers. Although the effect on GI cancers may be modified by ethnicity and cancer sites, small sample seizes of the subgroup analyses suggest that further larger studies are needed, especially for non-colorectal GI cancers in Caucasians and GI cancers in Asians.
Highlights
Gastrointestinal (GI) cancers are the common malignant tumors in the world [1,2], of which colorectal cancer is the third most common cancer in males and the second in females, with over 1.2 millions of new cases and 608,700 deaths occurred in 2008 [2]
The effect on GI cancers may be modified by ethnicity and cancer sites, small sample seizes of the subgroup analyses suggest that further larger studies are needed, especially for non-colorectal GI cancers in Caucasians and GI cancers in Asians
Human population-based or hospital-based association studies were included in this meta-analysis, if they met all the following criteria: (1) an independent, unrelated case-control, nested case-control, or cohort study, (2) the NAD(P)H:quinone oxidoreductase 1 (NQO1) 609C.T polymorphism was determined, (3) the outcome was GI cancers, (4) there were sufficient data for calculating an odds ratio (OR) with 95% confidence interval (CI), and (5) the study was reported in English
Summary
Gastrointestinal (GI) cancers are the common malignant tumors in the world [1,2], of which colorectal cancer is the third most common cancer in males and the second in females, with over 1.2 millions of new cases and 608,700 deaths occurred in 2008 [2]. The quinones are mainly derived from endogenous quinones, such as vitamin E quinone and ubiquinone, and exogenous quinones, such as exhaust gas, cigarette smoke or diet [23,24] This two-electron reduction prevents the formation of semiquinones and highly reactive oxygen species (ROS), protecting cells against oxidative stress, cytotoxicity, and mutagenicity [25]. In addition to its catalytic role in quinones, NQO1 has been reported to show superoxide scavenging activity and protective activity against procarcinogenic benzenes [26,27] Both in vivo and in vitro studies have demonstrated that NQO1 regulates the stability of the tumor suppressors p53 and p73, protecting them from 20S proteasomal degradation, which is important for eliminating damaged cells that are prone to cancer development [28,29, 30,31]. The functional polymorphism (rs1800566) in the NQO1 gene, a 609C.T substitution, leading to proline-toserine amino-acid and enzyme activity changes, has been implicated in cancer risk, but individually published studies showed inconclusive results
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