This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cadieux, B. Articles by Costello, J. F. Search for Related Content PubMed PubMed Citation Articles by Cadieux, B. Articles by Costello, J. F.

Genome-wide Hypomethylation in Human Glioblastomas Associated with Specific Copy Number Alteration, Methylenetetrahydrofolate Reductase Allele Status, and Increased Proliferation

The Brain Tumor Research Center, Departments of ¹ Neurological Surgery and ² Pathology, University of California, San Francisco, California

Requests for reprints: Joseph F. Costello, The Brain Tumor Research Center, Department of Neurological Surgery, University of California San Francisco, 2340 Sutter, Room N225, San Francisco, CA 94143-0875. Phone: 415-514-1183; Fax: 415-502-6779; E-mail: jcostello{at}cc.ucsf.edu.

Genome-wide reduction in 5-methylcytosine is an epigenetic hallmark of human tumorigenesis. Experimentally induced hypomethylation in mice promotes genomic instability and is sufficient to initiate tumorigenesis. Here, we report that global hypomethylation is common in primary human glioblastomas [glioblastoma multiforme (GBM)] and can affect up to an estimated 10 million CpG dinucleotides per haploid tumor genome. Demethylation involves satellite 2 (Sat2) pericentromeric DNA at chromosomes 1 and 16, the subtelomeric repeat sequence D4Z4 at chromosomes 4q and 10q, and interspersed Alu elements. Severe hypomethylation of Sat2 sequences is associated with copy number alterations of the adjacent euchromatin, suggesting that hypomethylation may be one factor predisposing to specific genetic alterations commonly occurring in GBMs. An additional apparent consequence of global hypomethylation is reactivation of the cancer-testis antigen MAGEA1 via promoter demethylation, but only in GBMs and GBM cell lines exhibiting a 5-methylcytosine content below a threshold of 50%. Primary GBMs with significant hypomethylation tended to be heterozygous or homozygous for the low-functioning Val allele of the rate-limiting methyl group metabolism gene methylenetetrahydrofolate reductase (MTHFR), or had a deletion encompassing this gene at 1p36. Tumors with severe genomic hypomethylation also had an elevated proliferation index and deletion of the MTHFR gene. These data suggest a model whereby either excessive cell proliferation in the context of inadequate methyl donor production from MTHFR deficiency promotes genomic hypomethylation and further genomic instability, or that MTHFR deficiency–associated demethylation leads to increased proliferative activity in GBM. (Cancer Res 2006; 66(17): 8469-76)

This article has been cited by other articles:

				M. Linnebank, A. Semmler, S. Moskau, Y. Smulders, H. Blom, and M. Simon The methylenetetrahydrofolate reductase (MTHFR) variant c.677C>T (A222V) influences overall survival of patients with glioblastoma multiforme Neuro-oncol, August 1, 2008; 10(4): 548 - 552. [Abstract] [Full Text] [PDF]

				K. Tsumagari, L. Qi, K. Jackson, C. Shao, M. Lacey, J. Sowden, R. Tawil, V. Vedanarayanan, and M. Ehrlich Epigenetics of a tandem DNA repeat: chromatin DNaseI sensitivity and opposite methylation changes in cancers Nucleic Acids Res., April 1, 2008; 36(7): 2196 - 2207. [Abstract] [Full Text] [PDF]

				T. A. Rauch, X. Zhong, X. Wu, M. Wang, K. H. Kernstine, Z. Wang, A. D. Riggs, and G. P. Pfeifer High-resolution mapping of DNA hypermethylation and hypomethylation in lung cancer PNAS, January 8, 2008; 105(1): 252 - 257. [Abstract] [Full Text] [PDF]

				V. K. Rajasekhar and M. Begemann Concise Review: Roles of Polycomb Group Proteins in Development and Disease: A Stem Cell Perspective Stem Cells, October 1, 2007; 25(10): 2498 - 2510. [Abstract] [Full Text] [PDF]

				R. M. Brena and J. F. Costello Genome-epigenome interactions in cancer Hum. Mol. Genet., April 15, 2007; 16(R1): R96 - R105. [Abstract] [Full Text] [PDF]