Human Molecular Genetics, 2003, Vol. 12, No. 13 1569-1578
DOI: 10.1093/hmg/ddg167
© 2003 Oxford University Press
Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions
1Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA 19140, USA, 2Eccles Institute of Human Genetics, University of Utah, 15 N 2030 E, Salt Lake City, UT 84112, USA, 3Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140, USA, 4Bucknell University, 701 Moore Avenue, Lewisburg, PA 17837, USA, 5Phillips Academy, 180 Main Street, Andover, MA 01810, USA and 6Department of Pathology and Laboratory Medicine, Temple University School of Medicine, 3307 North Broad Street, Philadelphia, PA 19140, USA
Received March 5, 2003; Accepted April 28, 2003
Loss of imprinting (LOI) has been observed in many types of human tumors and may be a predisposing event in some colon cancers. LOI is strongly associated with alteration of normal DNA methylation patterns in differentially methylated regions (DMRs) of affected loci but it is not known whether LOI is caused by stochastic, environmental or genetic factors. We have developed a simple, quantitative assay for measurement of allelic methylation ratios based on methylation-sensitive restriction endonuclease digestion of genomic DNA and ‘hot-stop’ PCR. We examined allelic methylation ratios at DMRs within the IGF2/H19- and IGF2R-loci in a panel of 48 three-generation families. We observed familial clustering of individuals with abnormal methylation ratios at the IGF2/H19 DMR, as well as stability of this trait over a period of nearly two decades, consistent with the possibility that constitutional LOI at this locus is due largely to genetic factors. At the IGF2R DMR, we observed more variability in the allelic methylation ratios over time but also observed familial clustering of abnormal methylation ratios. Overall, our observations at IGF2R suggest that shared genetic factors are responsible for a major fraction of inter-individual variability in parental origin-dependent epigenetic modifications. However, temporal changes also occur in isolated cases, as well as within multiple individuals in the same family, indicating that environmental factors may also play a role.
* To whom correspondence should be addressed. Tel: +1 2157077373; Fax: +1 2157071454; Email: sapienza{at}temple.edu
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