Journal Article

Functional polymorphisms, altered gene expression and genetic association link NRH:quinone oxidoreductase 2 to breast cancer with wild-type p53

Ke-Da Yu, Gen-Hong Di, Wen-Tao Yuan, Lei Fan, Jiong Wu, Zhen Hu, Zhen-Zhou Shen, Ying Zheng, Wei Huang and Zhi-Ming Shao

in Human Molecular Genetics

Volume 18, issue 13, pages 2502-2517
Published in print July 2009 | ISSN: 0964-6906
Published online April 2009 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddp171
Functional polymorphisms, altered gene expression and genetic association link NRH:quinone oxidoreductase 2 to breast cancer with wild-type p53

Show Summary Details

Preview

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 × 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 × 10−7 for 29 bp-I/D and 2.3 × 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.

Journal Article.  10560 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.