Up-regulation of Activation-Induced Cytidine Deaminase Causes Genetic Aberrations at the CDKN2b-CDKN2a in Gastric Cancer

被引:50
作者
Matsumoto, Yuko
Marusawa, Hiroyuki [1 ]
Kinoshita, Kazuo [2 ]
Niwa, Yoko [2 ]
Sakai, Yoshiharu [3 ]
Chiba, Tsutomu
机构
[1] Kyoto Univ, Dept Gastroenterol & Hepatol, Grad Sch Med, Sakyo Ku, Kyoto 6068507, Japan
[2] Shiga Med Ctr Res Inst, Shiga, Japan
[3] Kyoto Univ, Dept Gastrointestinal Surg, Grad Sch Med, Kyoto 6068507, Japan
关键词
Gastric Cancer; Activation-Induced Cytidine Deaminase; Genetic Alterations; Tumor-Related Genes; TUMOR-RELATED GENES; CLASS SWITCH RECOMBINATION; HELICOBACTER-PYLORI; C-MYC; HUMAN HEPATOCYTES; AID EXPRESSION; TRANSLOCATIONS; HYPERMUTATION; SUPPRESSOR; HYPERMETHYLATION;
D O I
10.1053/j.gastro.2010.07.010
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
BACKGROUND & AIMS: The DNA/RNA editing enzyme activation-induced cytidine deaminase (AID) is mutagenic and has been implicated in human tumorigenesis. Helicobacter pylori infection of gastric epithelial cells leads to aberrant expression of AID and somatic gene mutations. We investigated whether AID induces genetic aberrations at specific chromosomal loci that encode tumor-related proteins in gastric epithelial cells. METHODS: Human gastric epithelial cell lines that express activated AID and gastric cells from AID transgenic mice were examined for DNA copy number changes and nucleotide alterations. Copy number aberrations in stomach cells of H pylori-infected mice and gastric tissues (normal and tumor) from H pylori-positive patients were also analyzed. RESULTS: In human gastric cells, aberrant AID activity induced copy number changes at various chromosomal loci. In AID-expressing cells and gastric mucosa of AID transgenic mice, point mutations and reductions in copy number were observed frequently in the tumor suppressor genes CDKN2A and CDKN2B. Oral infection of wild-type mice with H pylori reduced the copy number of the Cdkn2b-Cdkn2a locus, whereas no such changes were observed in the gastric mucosa of H pylori-infected AID-deficient mice. In human samples, the relative copy numbers of CDKN2A and CDKN2B were reduced in a subset of gastric cancer tissues compared with the surrounding noncancerous region. CONCLUSIONS: H pylori infection leads to aberrant expression of AID and might be a mechanism of the accumulation of submicroscopic deletions and somatic mutations in gastric epithelial cells. AID-mediated genotoxic effects appear to occur frequently at the CDKN2b-CDKN2a locus and contribute to malignant transformation of the gastric mucosa.
引用
收藏
页码:1984 / 1994
页数:11
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