Possible Influence of GSTM1 and GSTT1 Null Genotype on the Risk for Development of Sporadic Colorectal Cancer

Abstract

ABSTRACTThe glutathione-S-transferases (GSTs) constitute a family of xenobiotic-metabolizing phase II enzymes, which mediate exposure to cytotoxic and genotoxic agents and may be involved in the susceptibility to cancer in general, and to colorectal cancers, particularly. For two of the genes, coding the cytoplasmic isoenzymes GST-mu and GST-theta (GSTM1 and GSTT1), null variant alleles have been found, in which the entire gene is absent. Investigations on the association of GSTs' null genotypes and colorectal cancer have reported quite controversial results.The aim of the current pilot study was to examine the relation of GSTM1 and GSTT1 homozygous null genotypes with colorectal cancer risk in a case-control study of Bulgarian patients. The GSTM1 and GSTT1 genotyping was conducted in 46 patients with colorectal carcinoma and 42 controls. A modified multiplex (duplex) PCR-based method was applied to assess the GSTs' genotypes.We observed a statistically significant case-control difference in the presence of GSTT1 null genotype (0.30 vs. 0.07, p=0.006), and only a tendency for prevalence of GSTM1 null genotype in CRC patient (0.57 vs. 0.36, p=0.052). The combined null genotypes were determined only in patients (0.20), whereas none of the control individual was with such genotype (p<0.0001). We found a 5.69-fold (95% CI, 1.59–20.00) and 2.34-fold (95% CI, 0.99–5.49) increased risk associated with GSTT1 and GSTM1 null genotypes, respectively and 21.53-fold (95% CI, 3.56–128.71) increased risk associated with the combined null genotypes. The colorectal cancer was diagnosed earlier in patients with GSTM1 null genotype and those patients had tumors in more advanced stage (III or IV) (p=0.033) and were with more aggressive phenotype, such as presence of lymph vessel invasion (p=0.042) than the patients with non-null genotype.In conclusion, based on our current results we suggest that the inherited absence of GST-theta alone or the simultaneous lack of GST-theta and GST-mu detoxifying enzymes due to the presence of homozygous null genotypes may be associated with development of sporadic colorectal cancer.