Cellular phenotypes of differentiated-type adenocarcinomas and precancerous lesions of the stomach are dependent on the genetic pathways.

To elucidate the relationship between genetic alterations and cellular phenotypes in differentiated-type carcinomas and precancerous lesions of the stomach, mutations of p53, APC and K-ras genes were examined, as well as microsatellite instability (MSI), in 52 tumours of the stomach. Tumours were selected with the following phenotypical features, using mucin histochemical and immunohistochemical analyses, in addition to their morphological features: (1) tumours with an extremely well-preserved gastric foveolar phenotype (foveolar-type); (2) tumours with an extremely well-preserved complete-type intestinal metaplastic phenotype (CIM-type); and (3) ordinary tumours without extreme phenotypes (ordinary-type). MSI occurred in 45% of foveolar-type, 24% of ordinary-type, and 0% of CIM-type tumours. p53 gene alterations occurred in 5% of foveolar-type, 18% of ordinary-type, and 31% of CIM-type. APC gene alterations were detected in 9% of foveolar-type, 6% of ordinary-type, and 0% of CIM-type. No K-ras gene mutation was detected in any of the three types. These results indicate that the genetic pathways are quite different among the phenotypes of tumours of the stomach. The 'mutator pathway', characterized by MSI, plays an important role in the tumourigenesis of foveolar-type, but not CIM-type tumours. The 'suppressor pathway', represented by p53 alteration, could participate in the tumourigenesis of the CIM-type, but is rare in foveolar-type tumours. Copyright 2000 John Wiley & Sons, Ltd.