APC, K-RAS CODON-12 MUTATIONS AND P53 GENE-EXPRESSION IN CARCINOMA AND ADENOMA OF THE GALLBLADDER SUGGEST 2 GENETIC PATHWAYS IN GALLBLADDERCARCINOGENESIS

Current histopathological evidence suggests that gall-bladder cancer h as two main morphological pathways for its development: de novo (ab in itio) origin and adenoma-carcinoma sequence. In order to investigate t he genetic difference between them, APC mutations were examined by RNa se protection analysis, K-ras mutations by nested polymerase chain rea ction-restriction fragment length polymorphism analysis, and p53 gene overexpression by immunohistochemical analysis in both tumors and beni gn lesions of the gall-bladder. Overexpression of the p53 gene was det ected in 105 of 164 (64%) de novo carcinomas regardless of size and de pth of invasion, but not in 16 tumors of carcinoma-in-pyloric-gland-ty pe adenoma, or in 51 adenomas (47 pyloric gland-type and 4 intestinal- type). K-ras codon 12 mutation was detected in 4 of 40 (10%) de novo c arcinomas, all four being associated with p53 gene overexpression, but not in 12 tumors of carcinoma in adenoma or 16 adenomas (14 pyloric g land-type and 2 intestinal-type). APC mutation was not found in 16 de novo carcinomas or the one pyloric gland-type adenoma examined. These results suggest that there are two distinct genetic pathways in gall-b ladder carcinogenesis; that is, de novo carcinoma develops from a pred ominant p53 alteration with low K-ras mutation, and carcinoma-in-pylor ic-gland-type adenoma develops from p53-, K-ras-, and APC-gene-unrelat ed, as yet unknown, alteration.