Polymorphism of glutathione S-transferase M3: interaction with glutathione S-transferase M1 and lung cancer susceptibility

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Abstract
GSTM3 is one of five mu-class genes (M1-M5) belonging to a cluster located in chromosome 1. GSTM3 has been found to be polymorphic in humans with a number of individuals presenting a 3 bp deletion within intron 6 (GSTM3*B). In this study we have addressed the possible role of the GSTM3 polymorphism on lung cancer susceptibility. GSTM3 was genotyped in a group of lung cancer patients (n=176) and in a control group of healthy smokers (n=175). The frequency distribution of GSTM3*A/GSTM3*A, GSTM3*A/GSTM3*B and GSTM3*B/GSTM3*B showed no significant differences between patients and controls. Allelism at GSTM3 was also analysed in combination with the GSTM1 polymorphism. The chi2 analysis confirmed that GSTM3*B allele is in linkage desequilibrium with GSTM1*A. The over-representation of GSTM1 null detected in previous studies, appeared to be restricted to those individuals with both GSTM1 null and GSTM3*A/GSTM3*A (48.3% in patients versus 36.0% in controls). The application of a second order logistic regression model revealed a significant adjusted odds ratio for the interaction term between GSTM1 null and GSTM3*A/GSTM3*A (OR: 2.14 95% CI 1.08-4.25) suggesting that this combined genotype may increase lung cancer risk. The analysis of transcription factor binding sites near the deleted sequence suggests that the heat-shock transcription factor 1 (HSTF1) could be involved in an enhanced expression of GSTM3*B, thus providing a possible mechanistic basis for a protective role of this allele.