Genetic analysis of colon tumors induced by a dietary carcinogen PhIP in CYP1A humanized mice: Identification of mutation of β-catenin/Ctnnb1 as the driver gene for the carcinogenesis

• Published in: Molecular carcinogenesis 2015-11, Vol.54 (11), p.1264-1274
• Main Authors: Wang, Hong, Zhou, Hong, Liu, Anna, Guo, Xiangyi, Yang, Chung S.
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - genetics; carcinogenesis; Carcinogenesis - genetics; Carcinogens - pharmacology; Colonic Neoplasms - genetics; colorectal cancer; Cytochrome P-450 CYP1A1 - genetics; Diet - adverse effects; driver mutation; exon sequencing; Exons - drug effects; Exons - genetics; Female; Genes, APC - drug effects; Genes, ras - drug effects; Genes, ras - genetics; Humans; Imidazoles - pharmacology; Male; Mice; Mutation - drug effects; Mutation - genetics; Wnt Signaling Pathway - genetics
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.22199

Replacing mouse Cyp1a with human CYP1A enables the humanized CYP1A mice to mimic human metabolism of the dietary carcinogen, 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP), by N2‐hydroxylation to a proximate carcinogen. Our previous study demonstrated that PhIP, combined with the dextrin sulfate sodium (DSS)‐induced colitis, induces colon carcinogenesis in hCYP1A mice. Here, we employed whole exome sequencing and found multiple gene mutations in PhIP/DSS‐induced colon tumors. Mutations in the exon 3 of Ctnnb1/β‐catenin, however, were the predominant events. We further sequenced the key fragments of Apc, Ctnnb1, and Kras, because mutations of these genes in the humans are commonly found as the drivers of colorectal cancer. Mutations on either codon 32 or 34 in the exon 3 of Ctnnb1 were found in 39 out of 42 tumors, but no mutation was found in either Apc or Kras. The sequence context of codons 32 and 34 suggests that PhIP targets +3G in a TGGA motif of Ctnnb1. Since mutations that activate Wnt signal is a major driving force for human colorectal cancers, we conclude that the mutated β‐catenin is the driver in PhIP/DSS‐induced colon carcinogenesis. This result suggests that the colon tumors in hCYP1A mice mimic human colorectal carcinogenesis not only in the dietary etiology involving PhIP, but also in the aberrant activation of the Wnt signaling pathway as the driving force. © 2014 Wiley Periodicals, Inc.