Glutathione-S-transferase gene polymorphisms in colorectal cancer patients: interaction between GSTM1 and GSTM3 allele variants as a risk-modulating factor

The distribution of polymorphisms in the glutathione S-transferase (GST) fa mily genes has been studied in 355 healthy controls and 206 cancer (59 prox imal and 147 distal) patients. All controls were subjected to flexible sigm oidoscopy, Odds ratios (OR) after stratification by age, gender and smoking were slightly higher in the cancer group as a whole for GSTM1-null (*0/*0) , GSTT1-null (*0/*0) and GSTM3 *A/*B or *B/*B when compared with the contro l group, but the differences did not reach statistical significance. GSTP1 variants had no effect. Separate analysis of patients with proximal and dis tal tumours has shown stronger associations for the distal cancers, the GST M3*B allele presence being significantly more frequent in these patients [O R = 1.77; 95 % confidence interval (CI) = 1,15-2,74], Taking into account s trong linkage between the GSTM1 *A and GSTM3*B alleles, a separate analysis of the GSTM1-nulled individuals was undertaken. The combination of GSTM1-n ull genotype with GSTM3*B allele presence (*A/*B or *B/*B) was significantl y overrepresented among patients with proximal and distal tumours taken tog ether(OR = 2.12; 95% CI = 1,24-3,63), and especially in distal cancer patie nts (OR = 2.75; 95% CI = 1.56-4.84), Male individuals displayed a stronger association between the presence of the GSTM1-null in combination with GSTM 3 *A/*B or *B/*B and distal tumours with a higher odds ratio (OR = 3.57; 95 % CI = 1.73-7.36), In contrast, the frequency of GSTM1 *B/*0 or *B/*B combi ned with GSTM3 *A/*A was significantly lower in patients with distal colore ctal cancer, especially in males (OR = 0.37; 95% CI = 0,15-0,92), Neither o f these combinations was associated with proximal tumours, Our findings sug gest that interactions of polymorphic genotypes within the GSTM gene cluste r affect individual susceptibility to colorectal carcinogenesis, the GSTM3* B variant presence being a risk factor especially in combination with the G STM1-null genotype.