Impact of GSTT1, GSTM1, GSTP1 and NAT2 genotypes on KRAS2 and TP53 gene mutations in colorectal cancer.

Which carcinogens are of influence in the development of human colorectal cancers remains a question; one answer could be the finding that specific polymorphisms in xenobiotic metabolizing enzymes are related to particular mutations in cancer genes. KRAS2 and TP53 gene mutations as well as genotypes for GSTM1, GSTP1, GSTT1 and NAT2 were determined in an exploratory series of 165 stable colorectal cancers. Mutations in KRAS2 and TP53 were found in 34% and 57.5% of cases, respectively. The KRAS2 mutation frequency was significantly lower in patients with a GSTT1 null genotype than in those with a GSTT1 non-null genotype (18% vs. 38%, p = 0.03). The overall risk of KRAS2 mutation for patients with distal colorectal cancer and GSTT1 null genotype was 0.3 (95% CI 0.1-0.9) compared to patients with distal colorectal cancer and non-null GSTT1 genotype. The overall risk of KRAS2 mutation was similarly reduced (OR = 0.4, 95% CI 0.2-0.9) for patients with distal colorectal cancer and GSTP1 mutated genotypes compared to patients with distal colorectal cancer and wild-type genotype. Patients with GSTP1 wild-type genotype appeared to be at significantly lower risk for TP53 mutation compared to patients with mutated genotypes (p = 0.023). Our results suggest that GSTT1 and GSTP1 could play a role in the occurrence of KRAS2 and TP53 mutations in colorectal cancer and generate a hypothesis on the dietary factors that could be incriminated. Copyright 2004 Wiley-Liss, Inc.