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Published Online February 24, 2005
Science DOI: 10.1126/science.1108080

Reports

Submitted on November 30, 2004
Accepted on January 13, 2005

Loss of Imprinting of Igf2 Alters Intestinal Maturation and Tumorigenesis in Mice

Takashi Sakatani 1, Atsushi Kaneda 1, Christine A. Iacobuzio-Donahue 2, Mark G. Carter 3, Sten de Boom Witzel 4, Hideyuki Okano 5, Minoru S. H. Ko 3, Rolf Ohlsson 6, Dan L. Longo 3, Andrew P. Feinberg 7

1 Department of Medicine
2 Department of Pathology; Department of Oncology
3 Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
4 Department of Pathology
5 Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
6 Department of Development and Genetics, Uppsala University, S-752 36 Uppsala, Sweden.
7 Department of Medicine; Department of Oncology; Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Loss of imprinting (LOI) of the insulin-like growth factor II gene (IGF2) is an epigenetic alteration that results in a modest increase in IGF2 expression, and it is present in the normal colonic mucosa of about 30% of patients with colorectal cancer. To investigate its role in intestinal tumorigenesis, we created a mouse model of Igf2 LOI by crossing female H19+/? mice with male Apc+/Min mice. Mice with LOI developed twice as many intestinal tumors as control littermates. Notably, these mice also showed a shift toward a less differentiated normal intestinal epithelium, reflected by an increase in crypt length and increased staining with progenitor cell markers. A similar shift in differentiation was seen in the normal colonic mucosa of humans with LOI. Thus, altered maturation of non-neoplastic tissue may be one mechanism by which epigenetic changes affect cancer risk.


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