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Functional polymorphisms, altered gene expression and genetic association link NRH:quinone oxidoreductase 2 to breast cancer with wild-type p53.
Hum Mol Genet. 2009 Jul 01; 18(13):2502-17.HM

Abstract

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.

Authors+Show Affiliations

Breast Surgery Department, Breast Cancer Institute, Cancer Hospital, Fudan University, Shanghai, PR China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19351655

Citation

Yu, Ke-Da, et al. "Functional Polymorphisms, Altered Gene Expression and Genetic Association Link NRH:quinone Oxidoreductase 2 to Breast Cancer With Wild-type P53." Human Molecular Genetics, vol. 18, no. 13, 2009, pp. 2502-17.
Yu KD, Di GH, Yuan WT, et al. Functional polymorphisms, altered gene expression and genetic association link NRH:quinone oxidoreductase 2 to breast cancer with wild-type p53. Hum Mol Genet. 2009;18(13):2502-17.
Yu, K. D., Di, G. H., Yuan, W. T., Fan, L., Wu, J., Hu, Z., Shen, Z. Z., Zheng, Y., Huang, W., & Shao, Z. M. (2009). Functional polymorphisms, altered gene expression and genetic association link NRH:quinone oxidoreductase 2 to breast cancer with wild-type p53. Human Molecular Genetics, 18(13), 2502-17. https://doi.org/10.1093/hmg/ddp171
Yu KD, et al. Functional Polymorphisms, Altered Gene Expression and Genetic Association Link NRH:quinone Oxidoreductase 2 to Breast Cancer With Wild-type P53. Hum Mol Genet. 2009 Jul 1;18(13):2502-17. PubMed PMID: 19351655.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional polymorphisms, altered gene expression and genetic association link NRH:quinone oxidoreductase 2 to breast cancer with wild-type p53. AU - Yu,Ke-Da, AU - Di,Gen-Hong, AU - Yuan,Wen-Tao, AU - Fan,Lei, AU - Wu,Jiong, AU - Hu,Zhen, AU - Shen,Zhen-Zhou, AU - Zheng,Ying, AU - Huang,Wei, AU - Shao,Zhi-Ming, Y1 - 2009/04/07/ PY - 2009/4/9/entrez PY - 2009/4/9/pubmed PY - 2009/8/14/medline SP - 2502 EP - 17 JF - Human molecular genetics JO - Hum Mol Genet VL - 18 IS - 13 N2 - 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. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/19351655/Functional_polymorphisms_altered_gene_expression_and_genetic_association_link_NRH:quinone_oxidoreductase_2_to_breast_cancer_with_wild_type_p53_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddp171 DB - PRIME DP - Unbound Medicine ER -