Abstract
Background: We hypothesized that NRH:quinone oxidoreductase 2 (NQO2) is a candidate susceptibility gene for breast cancer because of its known enzymatic activity on estrogen-derived quinones. A tri-allelic polymorphism in the NQO2 gene might be associated with the risk of luminal-like breast cancer. Methods: In this case-control study, 2,865 women were recruited, including 1,164 patients with pathologically confirmed breast cancer and 1,701 cancer-free controls. The tri-allelic genetic polymorphism (I-29, I-16, and D alleles) was genotyped by a polymerase chain reaction and restriction fragment length polymorphism (RFLP)-based assay. Because the I-16 allele frequency is rare (approximately 1.0%), individuals carrying the I-16 allele were excluded from the analysis. Breast cancer subtypes were classified according to ER, PR, HER2, and grade. Results: In the association analysis of allele, an increased risk of breast cancer is associated with I-29 allele [82.5% in case group and 79.0% in the control group; odds ratio (OR), 1.25; 95% CI, 1.09–1.43, compared with D allele, p = 0.0015]. In the association analysis of genotype, the I-29-containing genotype was significantly correlated with breast cancer under a dominant model (adjusted OR, 1.31, 95% CI, 1.12–1.54, p = 0.001). Moreover, in the subtype analysis, there was a significant association of the I-29/D polymorphism with luminal-like breast cancer (adjusted OR, 1.54, 95% CI, 1.22–1.94, p = 0.001 for luminal-A disease; adjusted OR, 1.37, 95% CI, 1.06–1.76, p = 0.014 for luminal-B disease) but not with HER2-enriched or triple-negative subtypes. Conclusion: The tri-allelic polymorphism in the NQO2 gene is associated with breast cancer risk, especially for the luminal-like subtype. Our findings provide a new piece of molecular epidemical evidence supporting the hypothesis that estrogen and its metabolites are carcinogens of luminal-like breast cancer. Further external validation studies are needed.
Highlights
Estrogen and its metabolites may play an essential role in breast carcinogenesis (Yager and Davidson, 2006)
We have reported that the frequencies of the I-29 allele and D allele are different between breast cancer cases and healthy controls, and that I-29 is a risk allele for breast cancer
The I-16 allele frequency is very low (1.5% in the control group and 1.0% in the case group), so it is difficult to reach a sufficient statistical power to detect the association between the I-16 allele and breast cancer risk
Summary
Estrogen and its metabolites may play an essential role in breast carcinogenesis (Yager and Davidson, 2006). Quinone oxidoreductase is a phase II detoxification enzyme that can neutralize carcinogens and catalyze the reduction of quinone metabolism. Gaikwad et al (2009) discovered for the first time that NQO2 could catalyze the reduction of estrogen quinone and act as a detoxification enzyme. They proved that NQO2 is faster than NQO1 in reducing estrogen quinone. It is logical to assume that NQO2 is a candidate gene for breast cancer susceptibility. We hypothesized that NRH:quinone oxidoreductase 2 (NQO2) is a candidate susceptibility gene for breast cancer because of its known enzymatic activity on estrogenderived quinones. A tri-allelic polymorphism in the NQO2 gene might be associated with the risk of luminal-like breast cancer
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