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Organ‐specific profiles of genetic changes in cancers caused by activation‐induced cytidine deaminase expression
Author(s) -
Morisawa Toshiyuki,
Marusawa Hiroyuki,
Ueda Yoshihide,
Iwai Akio,
Okazaki Ilmi,
Honjo Tasuku,
Chiba Tsutomu
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23853
Subject(s) - cytidine deaminase , biology , carcinogenesis , cancer research , cancer , downregulation and upregulation , gene , apobec , transgene , lung cancer , microbiology and biotechnology , genetics , pathology , medicine , genome
Abstract Various molecular changes characterizing organ‐specific carcinogenesis have been identified in human tumors; however, the molecular mechanisms of the genomic changes specific for each cancer are not well defined. A transgenic (Tg) mouse model with constitutive expression of the nucleotide‐editing enzyme, activation‐induced cytidine deaminase (AID), develops tumors in various organs as a result of the mutagenic activities of AID. This phenotypic character of AID Tg mice allowed us to analyze the organ‐specific genetic changes in tumor‐related genes commonly triggered by AID‐mediated mutagenesis. Among the 80 AID Tg mice analyzed, 11 mice developed hepatocellular carcinomas, and 7 developed lung cancers. In addition, 1 developed the gastric cancer and 3 developed gastric adenomas. Organ‐specific preferences for nucleotide changes were observed in some of the tumor‐related genes in each epithelial tissue of the AID Tg mice. Of note, the c‐myc and K‐ras genes were the preferential targets of the mutagenic activity of AID in lung and stomach cancers, respectively, whereas mutations in the p53 and β‐ catenin genes were commonly observed in all 3 organs. Quantitative RT‐PCR analyses revealed that alpha‐fetoprotein, insulin‐like growth factor2 and cyclin D1 genes were specifically upregulated in HCC, whereas upregulation of the matrix metalloproteinase7 gene was more marked in lung cancer. Our findings suggest that AID, a DNA mutator that plays a critical role linking inflammation to human cancers, might be involved in the generation of organ‐specific genetic diversity in oncogenic pathways during cancer development. © 2008 Wiley‐Liss, Inc.