AUTHOR=Zhou Jiao-Qun , Zhu Si-Yuan , He Ye , Yu Ke-Da 

TITLE=Association Between a Tri-allelic Polymorphism in the Estrogen Metabolism Oxidoreductase NRH:Quinone Oxidoreductase 2 Gene and Risk of Breast Cancer by Molecular Subtype

JOURNAL=Frontiers in Genetics

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.658285

DOI=10.3389/fgene.2021.658285

ISSN=1664-8021

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, 2865 women were recruited, including 1164 patients with pathologically confirmed breast cancer and 1701 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-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% confidence interval [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.
Conclusions:
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.