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Loss of Imprinting in Colorectal Cancer Linked to Hypomethylation of H19 and IGF2¹

Institute of Genetic Medicine and Department of Medicine [H. C., P. O., S. B., Y. W., A. P. F.], and Departments of Molecular Biology and Genetics, and Oncology Center [A. P. F.], Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and Departments of Urology and Biochemistry and Molecular Biology, University of Southern California School of Medicine, Los Angeles, California 90033 [C-L. H.]

Epigenetic alterations in human cancers include global DNA hypomethylation,gene hypomethylation and promoter hypermethylation, and loss of imprinting (LOI) of the insulin-like growth factor-II gene (IGF2). A mechanism for LOI described previously is hypermethylation of a differentially methylated region (DMR) upstream of the H19 gene, allowing activation of the normally silent maternal allele of IGF2. Here we show that this mechanism does not apply to colorectal cancers, which show hypomethylation of the H19 DMR as well as a DMR upstream of exon 3 of IGF2. This hypomethylation is found in both colorectal cancers and normal mucosa from the same patients, and in cell lines with somatic cell knockout of DNA methyltransferases DNMT1 and DNMT3B. These data suggest that hypomethylation is a mechanism for LOI, that the popular IGF2-H19 enhancer competition model for IGF2 imprinting does not apply to the human colon, and that an alternative model for LOI would involve a transcriptional repressor acting on the normally silent maternal allele of IGF2.

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