KRAS mutations predict progression of preneoplastic gastric lesions

Eight hundred sixty-three subjects with atrophic gastritis were recruited t o participate in an ongoing chemoprevention trial in Narino, Colombia, The participants were randomly assigned to intervention therapies, which includ ed treatment to eradicate Helicobacter pylori infection followed by daily d ietary supplementation with antioxidant micronutrients in a 2 x 2 x 2 facto rial design, A series of biopsies of gastric mucosa were obtained according to a specified protocol from designated locations in the stomach for each participant at baseline (before intervention therapy) and at year three, A systematic sample of 160 participants was selected from each of the eight t reatment combinations. DNA was isolated from each of these biopsies (n = 32 0), and the first exon of KRAS was amplified using PCR, Mutations in the KR AS gene were detected using denaturing gradient gel electrophoresis and con firmed by sequence analysis. Of all baseline biopsies, 14.4% (23 of 160) co ntained KRAS mutations, Among those participants with atrophic gastritis wi thout metaplasia, 19.4% (6 of 25) contained KRAS mutations, indicating that mutation of this important gene is likely an early event in the etiology o f gastric carcinoma, An important association was found between the presenc e of KRAS mutations in baseline biopsies and the progression of preneoplast ic lesions. Only 14.6% (20 of 137) of participants without baseline KRAS mu tations progressed from atrophic gastritis to intestinal metaplasia or from small intestinal metaplasia to colonic metaplasia; however, 39.1% (9 of 23 ) with baseline KRAS mutations progressed to a more advanced lesion after 3 years [univariate odds ratio (OR), 3.76 (P = 0.05); multivariate OR adjust ed for treatment, 3.74 (P = 0.04)]. In addition, the specificity of the KRA S mutation predicted progression. For those participants with G-->T transve rsions at position 1 of codon 12 (GGT-->TGT), 19.4% (5 of 17) progressed (u nivariate OR, 2.4); however, 60.0% (3 of 5) of participants with G-->A tran sitions at position 1 of codon 12 (GGT-->AGT) progressed (univariate OR, 8. 7; P = 0.004 using chi(2) test).