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Carcinogenesis Advance Access published online on September 4, 2006
Carcinogenesis, doi:10.1093/carcin/bgl161
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© 2006 The Author(s)
Received January 25, 2006
Revised August 23, 2006
Accepted August 25, 2006

CANCER BIOLOGY

Comprehensive DNA methylation profiling in a human cancer genome identifies novel epigenetic targets

J. M. Ordway 1, J. A. Bedell 1, R. W. Citek 1, A. Nunberg 1, A. Garrido 1, R. Kendall 2, J. R. Stevens 2, D. Cao 2, R. W. Doerge 2, Y. Korshunova 1, H. Holemon 1, J. D. McPherson 3, N. Lakey 1, J. Leon 1, R. A. Martienssen 4, and J. A. Jeddeloh 1 *

1 Orion Genomics, St. Louis, MO, USA
2 Department of Agronomy, Purdue University, W. Lafayette, IN, USA; Department of Statistics, Purdue University, W. Lafayette, IN, USA
3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
4 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY

* To whom correspondence should be addressed.
J. A. Jeddeloh, E-mail: jjeddeloh{at}oriongenomics.com


  Abstract

Using a unique microarray platform for cytosine methylation profiling, the DNA methylation landscape of the human genome was monitored at more than 21,000 sites, including 79% of the annotated transcriptional start sites (TSS). Analysis of an oligodendroglioma derived cell line LN-18 revealed more than 4,000 methylated TSS. The gene-centric analysis indicated a complex pattern of DNA methylation exists along each autosome, with a trend of increasing density approaching the telomeres. Remarkably, 2% of CpG islands (CGI) were densely methylated, and 17% had significant levels of 5mC, whether or not they corresponded to a TSS. Substantial independent verification, obtained from 95 loci, suggested that this approach is capable of large scale detection of cytosine methylation with an accuracy approaching 90%. In addition, we detected large genomic domains that are also susceptible to DNA methylation reinforced inactivation, such as the HOX cluster on chromosome 7 (CH7). Extrapolation from the data suggests that more than 2000 genomic loci may be susceptible to methylation and associated inactivation, and most have yet to be identified. Finally, we report six new targets of epigenetic inactivation (IRX3, WNT10A, WNT6, RAR{alpha}, BMP7, and ZGPAT). These targets displayed cell line and tumor specific differential methylation when compared with normal brain samples, suggesting they may have utility as biomarkers. Uniquely, hypermethylation of the CGI within an IRX3 exon was correlated with over-expression of IRX3 in tumor tissues and cell lines relative to normal brain samples.


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