A functional NQO1 609C>T polymorphism and risk of gastrointestinal cancers: a meta-analysis

Abstract

Background: The 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 findings: We 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.

Conclusions: This 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.

Figure 1. NQO1 gene structure and its function.

A. NQO1 gene structure and NQO1 609C>T polymorphism location. B. The multiple functions of NQO1. As depicted, NQO1 performs multiple functions within the cell, including two-electron reduction of quinones and their derivatives, stabilization of p53 and other tumor suppressors against proteasomal degradation, and scavenging of superoxide. NQO1 has also been implicated in maintaining microtubule integrity.

Figure 2. The flow chart of the included studies in the meta-analysis.

Figure 3. Forest plot (Fixed effects model) describing the association of the NQO1 609C>T polymorphism with risk of gastrointestinal (GI) cancers.

The NQO1 609C>T polymorphism was associated with a modestly increased risk of GI cancers in a dominant model (CT/TT vs. CC).

Figure 4. Funnel plot analysis to detect publication bias.

Each point represents an individual study for the indicated association.