APC, K-ras codon 12 mutations and p53 gene expression in carcinoma and adenoma of the gall-bladder suggest two genetic pathways in gall-bladder carcinogenesis.
Current histopathological evidence suggests that gall-bladder cancer has two main morphological pathways for its development: de novo (ab initio) origin and adenoma-carcinoma sequence. In order to investigate the genetic difference between them, APC mutations were examined by RNase protection analysis, K-ras mutations by nested polymerase chain reaction-restriction fragment length polymorphism analysis, and p53 gene overexpression by immunohisto-chemical analysis in both tumors and benign lesions of the gall-bladder. Overexpression of the p53 gene was detected in 105 of 164 (64%) de novo carcinomas regardless of size and depth of invasion, but not in 16 tumors of carcinoma-in-pyloric-gland-type 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 carcinomas, all four being associated with p53 gene overexpression, but not in 12 tumors of carcinoma in adenoma or 16 adenomas (14 pyloric gland-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-bladder carcinogenesis; that is, de novo carcinoma develops from a predominant p53 alteration with low K-ras mutation, and carcinoma-in-pyloric-gland-type adenoma develops from p53-, K-ras-, and APC-gene-unrelated, as yet unknown, alteration.
Itoi
T
T
First Department of Pathology, Niigata University School of Medicine, Japan.
Watanabe
H
H
Ajioka
Y
Y
Oohashi
Y
Y
Takel
K
K
Nishikura
K
K
Nakamura
Y
Y
Horil
A
A
Saito
T
T
D000236:Adenoma / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics*; D003062:Codon; D005706:Gallbladder Neoplasms / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D017491:Genes, APC; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D009154:Mutation
D003062:Codon