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

  • Epidemiology
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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 genoty** 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.

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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.

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Authors and Affiliations

  1. Department of Breast Surgery, Cancer Hospital/Cancer Institute, Breast Cancer Institute, Fudan University, 399 Ling-Ling Road, Shanghai, 200032, China

    Ke-Da Yu, Lei Fan, Gen-Hong Di, Ao-**ang Chen, Chen Yang, Jiong Wu, Zhen-Zhou Shen & Zhi-Ming Shao

  2. Institutes of Biomedical Science, Fudan University, Shanghai, 200032, China

    Ke-Da Yu, Lei Fan, Gen-Hong Di, Ao-**ang Chen, Chen Yang, Jiong Wu, Zhen-Zhou Shen & Zhi-Ming Shao

  3. Chinese National Human Genome Center at Shanghai, Shanghai, 201203, People’s Republic of China

    Wen-Tao Yuan & Wei Huang

  4. Shanghai Municipal Center for Disease Control and Prevention, Shanghai, 200336, People’s Republic of China

    Ying Zheng

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  1. Ke-Da Yu
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Correspondence to Zhi-Ming Shao.

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Ke-Da Yu, Lei Fan, and Gen-Hong Di have contributed equally to this work.

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Yu, KD., Fan, L., Di, GH. et al. Genetic variants in GSTM3 gene within GSTM4-GSTM2-GSTM1-GSTM5-GSTM3 cluster influence breast cancer susceptibility depending on GSTM1 . Breast Cancer Res Treat 121, 485–496 (2010). https://doi.org/10.1007/s10549-009-0585-9

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