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. Issue 11 (17th August 2014)

• Record Type: Journal Article
• Authors: Wang, Hong; Zhou, Hong; Liu, Anna; Guo, Xiangyi; Yang, Chung S.
• Is Part Of: Molecular carcinogenesis. Volume 54:Issue 11(2015:Nov.)
• Page Start: 1264
• Page End: 1274
• Publication Date: 2014-08-17
• Subjects: Carcinogenesis -- Molecular aspects -- Periodicals; 616.994071
• DOI: 10.1002/mc.22199
• Languages: English
• ISSNs: 0899-1987

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="mc22199-sec-0001" sec-type="section"> <p>Replacing mouse <italic>Cyp1a</italic> with human <italic>CYP1A</italic> 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<sup>2</sup>‐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 <italic>Ctnnb1</italic>/β‐catenin, however, were the predominant events. We further sequenced the key fragments of <italic>Apc</italic>, <italic>Ctnnb1</italic>, and <italic>Kras</italic>, 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 <italic>Ctnnb1</italic> were found in 39 out of 42 tumors, but no mutation was found in either <italic>Apc</italic> or <italic>Kras</italic>. The sequence context of codons 32 and 34 suggests that PhIP targets +3G in a TGGA motif of <italic>Ctnnb1</italic>. 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.</p> </sec> </abstract>