Human Molecular Genetics Advance Access originally published online on April 7, 2009
Human Molecular Genetics 2009 18(13):2502-2517; doi:10.1093/hmg/ddp171
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Functional polymorphisms, altered gene expression and genetic association link NRH:quinone oxidoreductase 2 to breast cancer with wild-type p53
1 Breast Surgery Department, Breast Cancer Institute, Cancer Hospital, Fudan University, Shanghai 200032, P.R. China 2 Department of Oncology, Institutes of Biomedical Science, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China 3 Chinese National Human Genome Center at Shanghai, Shanghai 201203, P.R. China 4 Shanghai Municipal Center for Disease Control and Prevention, Shanghai 200336, P.R. China
* To whom correspondence should be addressed at: Department of Breast Surgery, Cancer Hospital/Cancer Institute, Breast Cancer Institute, Fudan University, 399 Ling-Ling Road, Shanghai, 200032 China. Tel: +86 2164175590; Fax: +86 2164434556; Email: zhimingshao{at}yahoo.com
Received February 9, 2009; Revised March 31, 2009; Accepted April 3, 2009
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 and its ability to stabilize p53. We performed case–control studies to investigate the contributions of genetic variants/haplotypes of the NQO2 gene to breast cancer risk. In the first hospital-based study (n = 1604), we observed significant associations between the incidence of breast cancer and a 29 bp-insertion/deletion polymorphism (29 bp-I/D) and the rs2071002 (+237A>C) polymorphism, both of which are located within the NQO2 promoter region. Decreased risk was associated with the D-allele of 29 bp-I/D [odds ratio (OR), 0.76; P = 0.0027] and the +237C-allele of rs2071002 (OR, 0.80; P = 0.0031). Specifically, the susceptibility variants within NQO2 were notably associated with breast carcinomas with wild-type p53 (the most significant P-value: 3.3 x 10–6). The associations were successfully replicated in an independent population set (familial/early-onset breast cancer cases and community-based controls, n = 1442). The combined P-values of the two studies (n = 3046) are 3.8 x 10–7 for 29 bp-I/D and 2.3 x 10–6 for rs2071002. Furthermore, we revealed potential mechanisms of pathogenesis of the two susceptibility polymorphisms. Previous work has demonstrated that the risk-allele I-29 of 29 bp-I/D introduces transcriptional-repressor Sp3 binding sites. Using promoter reporter-gene assays and electrophoretic-mobility-shift assays, our present work demonstrated that the other risk-allele, +237A-allele of rs2071002, abolishes a transcriptional-activator Sp1 binding site. Furthermore, an ex vivo study showed that normal breast tissues harboring protective genotypes expressed significantly higher levels of NQO2 mRNA than those in normal breast tissues harboring risk genotypes. Taken together, the data presented here strongly suggest that NQO2 is a susceptibility gene for breast carcinogenesis.