Immunohistochemical expression of cell-cycle proteins in gastric precancerous lesions.

Background: The early indicator for the subject predisposed to gastric cancer is abnormal proliferation of gastric epithelial cells, such as atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia, which have been considered as precancerous lesions of gastric cancer. To determine whether p53 protein, cyclins D1, and D3, and p27(kip1) play a role in the carcinogenesis pathway of gastric cancer, we performed an immunohistochemical study of their expression in gastric precancerous lesions.

Methods: A total of 1 45 endoscopic gastric biopsy specimens of AG, IM, and gastric dysplasia were studied. These molecular markers were localized by immunohistochemistry.

Results: P53 was expressed in 15% of cases with gastric dysplasia and not in the pre-dysplastic stages of the gastric mucosa. All cases were concerning high-grade dysplasia. Cyclin D1 protein was almost undetectable in the precancerous lesions of gastric cancer. Cyclin D3 protein overexpression was seen in 10% of biopsies with IM, and 50% of biopsies with gastric dysplasia. High expression of p27(kip1) protein was demonstrated in all cases of chronic gastritis. As atrophy, IM, and dysplasia develop, expression of p27(kip1) protein is suppressed. In total, 15% of dysplastic cases showed no expression of p27(kip1) protein.

Conclusions: (i) P53 mutation must be a late event during the development of gastric cancer. (ii) Cyclin D1 protein overexpression may not play a role in the progression from normal to neoplastic gastric mucosa, while overexpression of cyclin D3 is an earlier event during gastric carcinogenesis, and its role must be further evaluated. (iii) Reduced expression of p27(kip1) is a rather early event in gastric tumorigenesis, before dysplastic changes occur.