The new understanding of two-sided role of glutathione S-transferase M1 in breast cancer susceptibility.

Abstract

Abstract Abstract #3098 [Background and purpose] Although glutathione S-transferase M1 (GSTM1) enzyme occupies a key position in biological detoxification processes by catalyzing the glutathione conjugation of carcinogens, GSTM1 gene is genetically deleted (referred as GSTM1-null or GSTM1-/-) in a high percentage of the Eurasian populations. Numerous studies have examined the association of GSTM1-/- with breast cancer yielding inconsistent results. In addition, few genetic variants in this gene have been explored. We set out to systematically evaluate the contributions of GSTM1 gene deletion/presence and common variants in GSTM1 to breast cancer, followed by functional studies.
 [Methods and Results] In the present study, we show that GSTM1-/- does confer a weak increased risk of breast cancer compared with GSTM1-present genotype, being confirmed by a meta-analysis of combining 40 related studies with the current case-control study (921 cases vs. 711 controls) of Chinese population (overall odds ratio of 1.10, 95% confidence interval: 1.04-1.15, P<0.001). Unexpectedly, GSTM1 homozygous wild-type (+/+) is also associated with a risk of breast cancer compared with heterozygous (+/-) individuals on the basis of accurate classification using long-PCR-based assay. Furthermore, for the population with one allele of GSTM1 (GSTM1+/-) accounting for 30-50%, we genotype four common single nucleotide polymorphisms (SNPs) spanning GSTM1 gene and identify a functional variant g.-498C>G in the putative promoter region associated with breast cancer risk. It displays that minor -498G allele is significantly more frequent in breast cancer controls than in cases (odds ratio of 0.51, 95% confidence interval: 0.30-0.86, P=0.012). This allele also leads to significantly reduced promoter activity compared to the major -498C allele. Further studies reveal the -498G can modify AP-2 binding site and decrease GSTM1 transcription. Among the three AP-2 isoforms, AP-2α provides the predominant regulation effect on this SNP.
 [Conclusions] These results indicate that the effect of GSTM1 genotypes conferring to breast cancer susceptibility is not dosage-dependent as taken for grant previously. GSTM1 has a two-sided role in breast cancer susceptibility; too high or too low expression of GSTM1 is not beneficial. We recommend that the complicated genetic predisposition of GSTM1 be considered when predicting breast cancer susceptibility using single or a panel of genetic variants. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3098.