This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hunt, J. D. Articles by Fontham, E. T. H. Search for Related Content PubMed PubMed Citation Articles by Hunt, J. D. Articles by Fontham, E. T. H.

KRAS Mutations Are Not Predictive for Progression of Preneoplastic Gastric Lesions¹

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

	Abstract

Top Abstract Introduction Materials and Methods Results and Conclusions References

 
Individuals with atrophic gastritis (n = 863) were recruited to participate in a chemoprevention trial in Nariño, Columbia. The volunteers were randomly assigned to intervention therapies, which included antibiotic treatment for Helicobacter pylori infection, and then daily dietary supplementation with antioxidant micronutrients in a 2³factorial design. Biopsies were obtained according to a specified protocol from designated areas in the stomach for each individual at baseline (before intervention therapy), at year 3, and at year 6. A systematic sample of 160 participants was selected from each of the eight treatment combinations, and the first exon of KRAS was examined for mutations. At year 3, the data indicated that individuals with KRAS mutations in their baseline premalignant stomach biopsies were 3.74 times as likely to progress to a higher premalignant stage than those who lacked baseline mutations (P = 0.04; C. Gong et al., Cancer Epidemiol. Biomark. Prev. 8:167–171, 1999). However, after 6 years, baseline KRAS mutations failed to predict histological progression. Also, KRAS mutation in 72-month biopsies did not predict histological progression.

	Introduction

Top Abstract Introduction Materials and Methods Results and Conclusions References

 
Sequential steps of precancerous changes often precede intestinal-type gastric carcinoma. These steps include atrophic gastritis, IM³ (type I, complete, or small intestinal metaplasia; and type III, incomplete, or colonic intestinal metaplasia), and dysplasia (reviewed in Ref. 1 ). Mutations in KRAS are detected in many types of human tumors and have been associated with development and progression (2) . Recently, we analyzed the KRAS mutation status of premalignant stomach biopsies taken at baseline and at 36 months from 160 individuals from Colombia who had a high risk for developing gastric cancer and were enrolled in a 2³ factorial intervention trial. In that study, we found that those with baseline KRAS mutations were 3.76 times more likely to progress from either atrophy to metaplasia or from complete metaplasia (type I) to incomplete metaplasia (type III; P = 0.05; Ref. 3 ). When the odds ratio was adjusted for intervention therapy, the estimate was unchanged and statistically significant (odds ratio, 3.74; P = 0.04). The presence of baseline KRAS mutations was a significant predictor of progression at 36 months.

In the present study, biopsies were taken from 142 of the 160 study subjects who returned for 72-month follow-ups. They were analyzed for KRAS mutation and for progression/regression of stomach lesions. The hypothesis: baseline KRAS mutations predict histological progression of premalignant stomach lesions.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results and Conclusions References

 
Study Population.
Eight hundred and sixty-three individuals with chronic multifocal atrophic gastritis were recruited from the towns of Pasto and Tuquerres of Nariño in the southern Colombian Andes. In this region, the incidence of gastric cancer ranks as one of the highest in the world (150/100,000; Ref. 4 ). The estimated Helicobacter pylori prevalence is >90% among asymptomatic adults (5) . The volunteers were agricultural or blue-collar workers of Spanish-Indian ("mestizo") extraction. The demographic characteristics of the volunteer population have been described previously (6) . Endoscopic evaluations of individuals from the community who volunteered to participate in the study were performed in the Hospital Departmental (Pasto, Colombia) after obtaining informed consent approved by the local Human Subjects Committee and the Louisiana State University Health Sciences Center Institutional Review Board. Infection with H. pylori was detected by the Steiner modification of the Warthin-Starry staining method using baseline biopsies.

Study Design.
Volunteer individuals were randomized into treatment groups using a 2³ factorial design as described previously (3) . A systematic sample of 160 participants was selected from each of the eight treatment combinations for this study. Of these 160 individuals, samples were available from 142 at 72 months. The anti-Helicobacter treatment consisted of a 2-week course of amoxicillin (500 mg, three times per day), metronidazole (400 mg, three times per day), and bismuth subsalicylate (262 mg, four times per day). Ascorbic acid (1-g tablet, twice per day) and/or ß-carotene (30-mg capsule, once per day) or matched placebos for these two drugs (provided by Hoffman-La Roche, Inc.) were given throughout the study. Compliance was assessed by quarterly pill-counts as well as by measurement of serum antioxidant levels at the time of the third endoscopy. Compliance was consistently >90%, as measured by pill-count. Biopsies from 160 individuals (20 from each group) were used to detect KRAS mutations in a double-blinded study at 36 months (3) . Biopsies, DNA isolation, mutation detection by denaturing gradient gel electrophoresis, DNA sequencing, and statistical analyses have all been described previously in detail (3) .

	Results and Conclusions

Top Abstract Introduction Materials and Methods Results and Conclusions References

 
Of the 160 original volunteers, histological diagnoses were available for 142 individuals after 72 months of follow-up. As seen in Table 1 , 12 of 142 (8.4%) progressed to a higher histological stage, 81 of 142 (57.0%) did not change, and 49 of 142 (34.5%) regressed. There was no association between histological change at the end of 6 years of follow-up and KRAS mutation status at baseline (P = 0.934). This was somewhat surprising, given our previous finding that baseline KRAS mutations strongly predicted histological progression after 36 months of follow-up (3) .

Given our encouraging preliminary study that indicated that the presence of detectable KRAS mutations at baseline was a strong predictor of future progression (3) , it is disappointing that after longer follow-up the association did not hold. Given the worldwide frequency of gastric cancer and the poor 5-year survival rate associated with this disease, a reliable prognostic indicator for the development of stomach cancer is badly needed.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported in part by Program Project Grant P01-CA28842 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Louisiana State University Health Sciences Center, Department of Biochemistry and Molecular Biology, 533 Bolivar St., CSB-4-18, New Orleans, LA 70112. Phone: (504) 568-4734; Fax: (504) 599-1014; E-mail: jhunt{at}lsuhsc.edu

³ The abbreviation used is: IM, intestinal metaplasia.

Received 9/15/00; accepted 10/24/00.

	References

Top Abstract Introduction Materials and Methods Results and Conclusions References

 

1. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process–First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res., 52: 6735-6740, 1992.[Abstract/Free Full Text]
2. Cooper, G. M. Guanine nucleotide binding proteins. In: Oncogenes, Ed. 2, pp. 222–242. Sudbury, MA: Jones and Bartlett Publishers, 1995.
3. Gong C., Mera R., Bravo J. C., Ruiz B., Diaz-Escamilla R., Fontham E. T. H., Correa P., Hunt J. D. KRAS mutations predict progression of preneoplastic gastric lesions. Cancer Epidemiol. Biomark. Prev., 8: 167-171, 1999.[Abstract/Free Full Text]
4. Correa P., Haenszel W., Cuello C., Zavala D., Fontham E., Zarama G., Tannenbaum S., Collazos T., Ruiz B. Gastric precancerous process in a high risk population: cross sectional studies. Cancer Res., 50: 4731-4736, 1990.[Abstract/Free Full Text]
5. Correa P., Muñoz N., Cuello C., Fox J., Zavala D., Ruiz B. The role of Camplyobacter pylori in gastro-duodenal disease Fenoglio-Preiser C. eds. . Progress in Surgical Pathology, : 191-210, Field & Wood Philadelphia 1989.
6. Mannick E. E., Bravo L. E., Zarama G., Realpe J. L., Zhang X-J., Ruiz B., Fontham E. T. H., Mera R., Miller M. J. S., Correa P. Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effects of antibiotics and antioxidants. Cancer Res., 56: 1996.

This article has been cited by other articles:

				J. G. Fox and T. C. Wang Helicobacter pylori -- Not a Good Bug after All N. Engl. J. Med., September 13, 2001; 345(11): 829 - 832. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hunt, J. D. Articles by Fontham, E. T. H. Search for Related Content PubMed PubMed Citation Articles by Hunt, J. D. Articles by Fontham, E. T. H.