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

Abstract

Mu class of Glutathione-S-transferase (GSTM) genes arrange in a tandem on chromosome lpl3.3. 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 accord-ing to the absence or presence of GSTMl. In the GSTM1-l-group, the allele frequency of one SNP in GSTM3 was sig-nificantly different between cases and controls (P = 2.0 x 10 -4, corrected P = 0.001), with odds ratio of 1.75 (95% confidence interval, 1.26-2.44). The observed asso-ciation in the GSTM1-l- 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 epidemio-logical 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 geno-types 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 GSTMl is absent. We infer that GSTM3 catalyzing ability in normal breast tissue might protect against breast carcinogenesis. © Springer Science+Business Media, LLC. 2009.