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Breast Cancer Research and Treatment

, Volume 121, Issue 2, pp 485–496 | Cite as

Genetic variants in GSTM3 gene within GSTM4-GSTM2-GSTM1-GSTM5-GSTM3 cluster influence breast cancer susceptibility depending on GSTM1

  • Ke-Da Yu
  • Lei Fan
  • Gen-Hong Di
  • Wen-Tao Yuan
  • Ying Zheng
  • Wei Huang
  • Ao-Xiang Chen
  • Chen Yang
  • Jiong Wu
  • Zhen-Zhou Shen
  • Zhi-Ming Shao
Epidemiology

Abstract

Mu class of Glutathione-S-transferase (GSTM) genes arrange in a tandem on chromosome 1p13.3. The relationship between genetic variants in the GSTM1-5 gene cluster and breast cancer is still ambiguous. In the present study, 17 tagging single-nucleotide polymorphisms (SNPs) covering the GSTMs cluster were originally selected and 11 validated SNPs were used for genotyping 921 cases and 711 controls. The association analyses were performed according to the absence or presence of GSTM1. In the GSTM1−/− group, the allele frequency of one SNP in GSTM3 was significantly different between cases and controls (P = 2.0 × 10−4, corrected P = 0.001), with odds ratio of 1.75 (95% confidence interval, 1.26–2.44). The observed association in the GSTM1−/− group was successfully replicated in an independent population set (familial/early-onset breast cancer cases, n = 267; community-based controls, n = 667). The combined P values were robust (10−6) and the false positive report probability (FPRP) values were low. In contrast, no susceptibility allele/haplotype was identified when the GSTM1 gene was present. Based on epidemiological observations, we further identified two genetic variants in the GSTM3 locus accounting for differential expression of GSTM3 in normal breast tissues by such means as altering binding of RNA-pol-II. Protective genotypes were correlated with higher GSTM3 expression levels. In conclusion, SNPs/haplotypes in the GSTM3 gene within the GSTMs gene cluster are likely to contribute to breast cancer risk when the GSTM1 is absent. We infer that GSTM3 catalyzing ability in normal breast tissue might protect against breast carcinogenesis.

Keywords

Breast cancer Genetic susceptibility Glutathione-S-transferase Gene cluster 

Notes

Acknowledgments

This research is supported by grants from the National Basic Research Program of China (2006CB910501), the National Natural Science Foundation of China (30971143, 30972936), and the Shanghai Science and Technology Committee (06DJ14004, 06DZ19504). We thank the studied women for their willingness to cooperate with our study, and we are also grateful to two anonymous reviewers for their very helpful suggestions and valuable comments.

Supplementary material

10549_2009_585_MOESM1_ESM.docm (385 kb)
Supplementary material 1 (DOCM 385 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Ke-Da Yu
    • 1
    • 2
  • Lei Fan
    • 1
    • 2
  • Gen-Hong Di
    • 1
    • 2
  • Wen-Tao Yuan
    • 3
  • Ying Zheng
    • 4
  • Wei Huang
    • 3
  • Ao-Xiang Chen
    • 1
    • 2
  • Chen Yang
    • 1
    • 2
  • Jiong Wu
    • 1
    • 2
  • Zhen-Zhou Shen
    • 1
    • 2
  • Zhi-Ming Shao
    • 1
    • 2
  1. 1.Department of Breast Surgery, Cancer Hospital/Cancer Institute, Breast Cancer InstituteFudan UniversityShanghaiChina
  2. 2.Institutes of Biomedical ScienceFudan UniversityShanghaiChina
  3. 3.Chinese National Human Genome Center at ShanghaiShanghaiPeople’s Republic of China
  4. 4.Shanghai Municipal Center for Disease Control and PreventionShanghaiPeople’s Republic of China

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