Journal Article

IL-10 deficiency leads to somatic mutations in a model of IBD

Yuichirou Sato, Seiichi Takahashi, Yoshitaka Kinouchi, Manabu Shiraki, Katsuya Endo, Yoshifumi Matsumura, Yoichi Kakuta, Masaki Tosa, Atsuhiro Motida, Hiroko Abe, Go Imai, Hiroshi Yokoyama, Eiki Nomura, Kenichi Negoro, Sho Takagi, Hiroyuki Aihara, Ken-ichi Masumura, Takehiko Nohmi and Tooru Shimosegawa

in Carcinogenesis

Volume 27, issue 5, pages 1068-1073
Published in print May 2006 | ISSN: 0143-3334
Published online January 2006 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgi327

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Individuals with inflammatory bowel disease (IBD) are at increased risk of developing gastrointestinal cancer. Here, we have tested the possibility that chronic inflammation could trigger mutations. For this, we have used IL-10-deficient (IL-10−/−) mice, which spontaneously develop intestinal inflammation, in combination with a transgenic gpt gene and red/gam gene (gpt+IL-10−/−), which is a well-characterized mutation reporter locus. The total mutation frequency in the colon of gpt+IL-10−/− mice was about five times higher than that in normal gpt+IL-10+/+ mice. In the particular case of G:C to A:T transitions, the frequency of mutations in gpt+IL-10−/− mice was 4.1 times higher than that in control mice. Interestingly, the frequency of small deletions and insertions was also strikingly increased (∼10 times). The majority of the deletion or insertion mutations were observed in the monotonous base runs or adjacent repeats of short tandem sequences. In contrast, the frequency of large deletions, detected by loss of the Spi marker present in the red/gam transgene, was similar among the mouse strains. Finally, as a control, the mutation frequency in non-inflamed tissues, such as the liver, were similar between gpt+IL-10−/− mice and gpt+IL-10+/+ mice. Our data demonstrate that the chronic inflammatory environment in the colon promotes the generation of mutations.

Keywords: FAP, familial adenomatous polyposis; Spi, sensitive to P2 interference; 6-TG, 6-thioguanine; TGF-β1, transforming growth factor-β1; UC, ulcerative colitis

Journal Article.  3957 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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