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

Abstract

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 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 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.

Absence of mutation in the putative tumor-suppressor gene KLF6 in colorectal cancers

“…It is not likely to be due to a failure in our mutation screening method since its sensitivity has been previously validated in a larger series of tumor DNA samples including those presently reported by the identification of TP53 and KRAS2 gene mutations in 51 and 37% of the cases (Ferraz et al, 2004). These frequencies of TP53 and KRAS mutations are similar to that reported in previous published series of CRC (Hamelin et al, 1994;Andreyev et al, 1998;Smith et al, 2002).…”

Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer

“…This mutation (c.40G>A, p.V14I) has previously been described in a limited number of colorectal tumors (Ferraz et al, 2004;Ahlquist et al, 2008;He et al, 2009) and may be pathogenic based on studies showing the recombinant protein containing this mutation to have reduced GTPase activity (Schubbert et al, 2006) and to increase colony growth (Schubbert et al, 2006;Tyner et al, 2009). We also detected a novel 6-bp insertion representing a tandem duplication of KRAS codons 10 and 11 in two patients.…”

High-Resolution Melting Analysis as a Sensitive Prescreening Diagnostic Tool to Detect KRAS, BRAF, PIK3CA, and AKT1 Mutations in Formalin-Fixed, Paraffin-Embedded Tissues

“…28 We have found an insertion mutation of KRAS codon 13 (G13_V14insG) and a point mutation (V14A), both of which had not yet been described, to the best of our knowledge. However, KRAS V14I mutations have been described in colorectal cancer, 29 myeloid leukemia, 30 and in 3 patients with Noonan syndrome. 31 Functional assays revealed the oncogenic properties of the V14I mutation in comparison to wild-type KRAS.…”