More Frequent β‐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 β‐catenin/Tcf pathway. Although it is thought that alterations in APC and β‐catenin may complement one another, the contribution of β‐catenin mutations to colorectal carcino‐genesis remains unclear. We therefore performed PCR‐single strand conformation polymorphism analysis and direct sequencing of exon 3 of β‐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[4,5b]pyridine (PhIP) treated F344 rats. β‐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‐3β. 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 β‐catenin mutations in adenomas was significantly higher than in ACF (P < 0.001) and adenocarcinomas (P < 0.05). Thus, β‐catenin mutations may have more importance in the genesis of adenomas than ACF or adenocarcinomas in rat colon carcinogens by PhIP.