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

Abstract

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. 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. 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. 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.