NO EVIDENCE FOR FUNCTIONAL INACTIVATION OF WILD-TYPE P53 PROTEIN BY MDM2 OVEREXPRESSION IN GASTRIC CARCINOGENESIS

Inactivation of wild-type p53 during gastric carcinogenesis is usually caused by mutations within exons 5-8 of the p53 gene leading to mutat ed, usually immunohistochemically detectable p53 proteins, However, fu nctional inactivation of wild-type p53, mimicking mutational inactivat ion, may also result from binding to overexpressed MDM2 protein, While these two mechanisms of p53 inactivation are considered to be mutuall y exclusive, no data exist as to whether MDM2 overexpression occurs du ring gastric carcinogenesis. MDM2 protein overexpression was therefore studied in relation to p53 protein accumulation in gastric carcinogen esis. Forty-five paraffin-embedded gastrectomy specimens from early ga stric carcinomas were examined for the presence of chronic active gast ritis, chronic atrophic gastritis, subtypes of intestinal metaplasia, and dysplasia, The Lauren type was reassessed for all early carcinomas . p53 protein accumulation was examined using the monoclonal antibody DO-7. MDM2 protein overexpression was assessed with the monoclonal ant ibody SMP-14. Complete absence of nuclear p53 protein accumulation was observed in chronic active gastritis, chronic atrophic gastritis, and intestinal metaplasia, irrespective of the subtype, In gastric dyspla sia (one mild, two moderate, one severe), only severe dysplasia was p5 3-positive, Intestinal-type (n=20) and diffuse-type early gastric carc inoma (n=25) were p53-positive in 70 and 52 per cent of the cases, res pectively. MDM2 protein overexpression was not observed during gastric carcinogenesis, either in the p53-positive or in the p53-negative cas es, In conclusion, it appears that functional inactivation of wild-typ e p53 by MDM2 protein overexpression plays no role in (early) gastric carcinogenesis. (C) 1998 John Wiley & Sons, Ltd.