More frequent beta-catenin gene mutations in adenomas than in aberrant crypt foci or adenocarcinomas in the large intestines of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-treated rats.
Alteration of adenomatous polyposis coli (APC) is known to be an early event in neoplasia, causing activation of the beta-catenin / Tcf pathway. Although it is thought that alterations in APC and beta- catenin may complement one another, the contribution of beta-catenin mutations to colorectal carcinogenesis remains unclear. We therefore performed PCR-single strand conformation polymorphism analysis and direct sequencing of exon 3 of beta-catenin gene in adenomas, adenocarcinomas, and aberrant crypt foci (ACF), considered to be putative precursor lesions of colorectal neoplasias, in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) treated F344 rats. beta-Catenin mutations were identified in all of 7 adenomas (100%) and 6 of 12 (50%) adenocarcinomas. All of the mutations were found in codons 32 through 34, the serine encoded by codon 33 being an important phosphorylation site by glycogen synthase kinase-3beta. Regarding ACF, 14 of 46 (30.4%) were found to be mutated, eleven (78%) in codon 34, and the others in codon 45 (frequently altered in human colon cancer), and codons 47 and 56 (which have not been previously reported). The frequency of beta-catenin mutations in adenomas was significantly higher than in ACF (P < 0.001) and adenocarcinomas (P < 0.05). Thus, beta-catenin mutations may have more importance in the genesis of adenomas than ACF or adenocarcinomas in rat colon carcinogens by PhIP.
Tsukamoto
T
T
Laboratory of Pathology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan. ttsukamt@aichi-cc.pref.aichi.jp
Tanaka
H
H
Fukami
H
H
Inoue
M
M
Takahashi
M
M
Wakabayashi
K
K
Tatematsu
M
M
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics*; D000236:Adenoma / Q000139:chemically induced / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004273:DNA, Neoplasm / Q000032:analysis; D007093:Imidazoles; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D051381:Rats; D011916:Rats, Inbred F344; D015534:Trans-Activators; D051176:beta Catenin
C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D007093:Imidazoles; D015534:Trans-Activators; D051176:beta Catenin; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine