AIM:Disruption of cell cycle regulation is a critical event incarcinogenesis,and alteration of the retinoblastoma (pRb)tumour suppressor pathway is frequent.The aim of thisstudy was to compare alterations in this pathway in proximaland distal gastric carcinogenesis in an effort to explain theobserved striking epidemiological differences.METHODS:Immunohistochemistry was performed toinvestigate expression of p16 and pRb in the followinggroups of both proximal (cardia) and distal (antral) tissuesamples:(a) biopsies showing normal mucosa,(b) biopsiesshowing intestinal metaplasia and,(c) gastric cancerresection specimens including uninvolved mucosa andtumour.RESULTS:In the antrum there were highly significanttrends for increased p16 expression with concomitant (andin the group of carcinomas inversely proportional)decreased pRb expression from normal mucosa to intestinalmetaplasia to uninvolved mucosa (from cancer resections)to carcinoma.In the cardia,there were no differences inp16 expression between the various types of tissue sampleswhereas pRb expression was higher in normal mucosacompared with intestinal metaplasia and tissue fromcancer resections.CONCLUSION:Alterations in the pRb pathway appear toplay a more significant role in distal gastric carcinogenesis.It may be an early event in the former location since thetrend towards p16 overexpression with concomitant pRbunderexpression was seen as early as between normalmucosa and intestinal metaplasia.Importantly,the markeddifferences in expression of pRb and p16 between thecardia and antrum strongly support the hypothesis thatturnouts of the two locations are genetically different whichmay account for some of the observed epidemiologicaldifferences. AIM: Disruption of cell cycle regulation is a critical event incarcinogenesis, and alteration of the retinoblastoma (pRb) tumor suppressor pathway is ever. The aim of this study was to compare alterations in this pathway in proximaland distal gastric carcinogenesis in an effort to explain theobserved striking epidemiological differences. METHODS: Immunohistochemistry was performed to investigate expression of p16 and pRb in the following groups of both proximal (cardia) and distal (antral) tissues samples: (a) biopsies showing normal mucosa, (b) biopsiesshowing intestinal metaplasia and, (c) cancerresection specimens including uninvolved mucosa andtumor.RESULTS: In the antrum there were highly significanttrends for increased p16 expression with concomitant (and in the group of carcinomas inversely proportional) decreased pRb expression from normal mucosa to intestinalmetaplasia to uninvolved mucosa (from cancer resections) to carcinoma. In the cardia, there were no differences inp16 expressi on between the various types of tissue samples whereas pRb expression was higher in normal mucosacompared with intestinal metaplasia and tissue from cancer Resections. CONCLUSION: Alterations in the pRb pathway appear to play a more significant role in distal gastric carcinogenesis. It may be an early event in the former location since thetrend towards p16 overexpression with concomitant pRbunderexpression was seen as early as between between normalmucosa and intestinal metaplasia. Implantantly, the markeddifferences in expression of pRb and p16 between thecardia and antrum strongly support the hypothesis thatturnouts of the two locations are genetically different different whichmay account for some of the observed epidemiological differences.