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 N(2) -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.