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Carcinogenesis Advance Access published online on January 10, 2006
Carcinogenesis, doi:10.1093/carcin/bgi327
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received July 29, 2005
Revised September 5, 2005
Accepted December 20, 2005

CARCINOGENESIS

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

Yuichirou Sato 1 *, Seiichi Takahashi 1, Yoshitaka Kinouchi 1, Manabu Shiraki 1, Katsuya Endo 1, Yoshifumi Matsumura 1, Yoichi Kakuta 1, Masaki Tosa 1, Atsuhiro Motida 1, Hiroko Abe 1, Go Imai 1, Hiroshi Yokoyama 1, Eiki Nomura 1, Kenichi Negoro 1, Sho Takagi 1, Hiroyuki Aihara 1, Ken-ichi Masumura 2, Takehiko Nohmi 2, and Tooru Shimosegawa 1

1 Department of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
2 Division of Genetics and Mutagenesis, National Institute of Health Sciences, Tokyo, Japan

* To whom correspondence should be addressed.
Yuichirou Sato, E-mail: ysatou{at}int3.med.tohoku.ac.jp


  Abstract

Individuals with inflammatory bowel disease 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 5 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 in control mice. Interestingly, the frequency of small deletions and insertions was also strikingly increased (about 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 were similar between 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: chronic inflammation; carcinogenesis; IL-10 knockout mouse; gpt delta transgenic mouse; deletion.
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