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KRAS Mutations Predict Progression of Preneoplastic Gastric Lesions¹

Departments of Biochemistry and Molecular Biology [C. G., J. D. H.], Pathology [R. M., J. C. B., B. R., R. D. E., E. T. H. F., P. C.], and Public Health and Preventive Medicine [E. T. H. F.], and the Stanley S. Scott Cancer Center [R. M., E. T. H. F., P. C., J. D. H.], Louisiana State University Medical Center, New Orleans, Louisiana 70112

Eight hundred sixty-three subjects with atrophic gastritis were recruited to participate in an ongoing chemoprevention trial in Nariño, Colombia. The participants were randomly assigned to intervention therapies, which included treatment to eradicate Helicobacter pylori infection followed by daily dietary supplementation with antioxidant micronutrients in a 2 x 2 x 2 factorial 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 treatment combinations. DNA was isolated from each of these biopsies (n = 320), and the first exon of KRAS was amplified using PCR. Mutations in the KRAS gene were detected using denaturing gradient gel electrophoresis and confirmed by sequence analysis. Of all baseline biopsies, 14.4% (23 of 160) contained KRAS mutations. Among those participants with atrophic gastritis without metaplasia, 19.4% (6 of 25) contained KRAS mutations, indicating that mutation of this important gene is likely an early event in the etiology of gastric carcinoma. An important association was found between the presence of KRAS mutations in baseline biopsies and the progression of preneoplastic lesions. Only 14.6% (20 of 137) of participants without baseline KRAS mutations 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 adjusted for treatment, 3.74 (P = 0.04)]. In addition, the specificity of the KRAS mutation predicted progression. For those participants with GT transversions at position 1 of codon 12 (GGTTGT), 19.4% (5 of 17) progressed (univariate OR, 2.4); however, 60.0% (3 of 5) of participants with GA transitions at position 1 of codon 12 (GGTAGT) progressed (univariate OR, 8.7; P = 0.004 using ² test).

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