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Organ-specific profiles of genetic changes in cancers caused by activation-induced cytidine deaminase expression

Toshiyuki Morisawa1, Hiroyuki Marusawa, Yoshihide Ueda

  • 1Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

International Journal of Cancer
|September 11, 2008
PubMed

Insights

Activation-induced cytidine deaminase (AID) causes organ-specific mutations in tumor genes. This DNA mutator may drive cancer diversity by altering oncogenic pathways, linking inflammation to cancer development.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • Organ-specific molecular changes in human tumors are known, but the mechanisms driving cancer-specific genomic alterations remain unclear.
  • Activation-induced cytidine deaminase (AID) is a nucleotide-editing enzyme whose mutagenic activity can induce tumors.
  • Transgenic (Tg) mouse models expressing AID offer a platform to study organ-specific genetic changes in carcinogenesis.

Purpose of the Study:

  • To investigate the organ-specific genetic alterations induced by activation-induced cytidine deaminase (AID) in a transgenic mouse model.
  • To identify common and organ-specific mutations in tumor-related genes caused by AID-mediated mutagenesis.
  • To explore the role of AID in generating genetic diversity within oncogenic pathways during cancer development.

Main Methods:

  • Analysis of tumor-related gene mutations in various organs of 80 AID Tg mice.
  • Genomic sequencing and quantitative RT-PCR to identify mutations and gene expression changes.
  • Comparative analysis of mutational patterns across hepatocellular carcinoma, lung cancer, and gastric cancer/adenomas.

Main Results:

  • AID Tg mice developed tumors in multiple organs, including liver (11/80), lung (7/80), and stomach (1/80 cancer, 3/80 adenomas).
  • Organ-specific mutational preferences were observed; c-myc and K-ras were targeted in lung and stomach cancers, respectively.
  • p53 and beta-catenin mutations were common across all three organs, while specific gene upregulations (AFP, IGF-2, CCND1 in HCC; MMP-7 in lung cancer) indicated organ-specific responses.

Conclusions:

  • AID, a DNA mutator, contributes to the generation of organ-specific genetic diversity in oncogenic pathways.
  • These findings suggest AID plays a critical role in linking inflammation to cancer development through mutagenic activities.
  • The study highlights the potential involvement of AID in the molecular mechanisms underlying organ-specific carcinogenesis.

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