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[Cancer Research 62, 1296-1299, March 1, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

Complete Genetic Suppression of Polyp Formation and Reduction of CpG-Island Hypermethylation in ApcMin/+ Dnmt1-Hypomorphic Mice1

Cindy A. Eads, Andrea E. Nickel and Peter W. Laird2

Departments of Biochemistry and Molecular Biology [C. A. E., P. W. L.] and Surgery [A. E. N., P. W. L.], University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, Room 6418, Los Angeles, California 90089-9176

Promoter CpG island hypermethylation of critical genes is thought to play an important role in human colorectal tumorigenesis. In this study, we show that low levels of CpG island methylation occur in the normal intestinal mucosa of ApcMin/+ mice and are increased in Multiple Intestinal Metaplasia (Min) polyps. We examined the interaction between CpG island hypermethylation and tumorigenesis by genetically modulating expression levels of the predominant DNA methyltransferase, Dnmt1, in ApcMin/+ mice. We show that a combination of Dnmt1 hypomorphic alleles results in the complete suppression of polyp formation and an accompanying reduction in the frequency of CpG island methylation in both the normal intestinal mucosa and intestinal adenomas. These results suggest that sufficient DNA methyltransferase expression is a prerequisite for polyp formation and that hypomorphic alleles of Dnmt1 are not merely genetic modifiers but the first identified true genetic suppressors of the Min phenotype.




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