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Originally published in Science Express on 24 February 2005
Science 25 March 2005:
Vol. 307. no. 5717, pp. 1976 - 1978
DOI: 10.1126/science.1108080
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Reports

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

Takashi Sakatani,1* Atsushi Kaneda,1* Christine A. Iacobuzio-Donahue,2,3* Mark G. Carter,5 Sten de Boom Witzel,2 Hideyuki Okano,6 Minoru S. H. Ko,5 Rolf Ohlsson,7 Dan L. Longo,5 Andrew P. Feinberg1,3,4{dagger}

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 did 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 nonneoplastic tissue may be one mechanism by which epigenetic changes affect cancer risk.

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

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: afeinberg{at}jhu.edu

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