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 mutation!; as well as genotypes for GSTMI, GSTPI, GSTTI 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 GSTTI null genotype than in those with a GSTTI non-null genotype (18% vs. 38%, p = 0.03). The overall risk of KRAS2 mutation for patients with distal colorectal cancer and GSTTI null genotype was 0.3 (95% Cl 0.1-0.9) compared to patients with distal colorectal cancer and non-null GSTTI genotype. The overall risk of KRAS2 mutation was similarly reduced (OR = 0.4, 95% Cl 0.2-0.9) for patients with distal colorectal cancer and GSTPI mutated genotypes compared to patients with distal colorectal cancer and wild-type genotype. Patients with GSTPI wildtype genotype appeared to be at significantly lower risk for TP53 mutation compared to patients with mutated genotypes (p = 0.023). Our results suggest that GSTTI and GSTPI 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. (C) 2004 Wiley-Liss, Inc.