Abstract

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 approximately 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.

Highlights

  • Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and is characterized by a median survival of f1 year for newly diagnosed cases [1]

  • The genomic 5-methylcytosine content of 10 primary GBMs (WHO grade 4 astrocytoma) and six glioma cell lines was measured by methyl acceptance and compared with values obtained for normal adult brain

  • We found that DNA methylation content of satellite 2 (Sat2) was higher than that of D4Z4 repeats in brain, whereas interspersed Alu elements collectively showed a 5-methylcytosine content intermediate to juxtacentromeric and subtelomeric satellite end regions, with values ranging from 82% to 84% (Fig. 2A)

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Summary

Introduction

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and is characterized by a median survival of f1 year for newly diagnosed cases [1]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Ching: Department of Internal Medicine and Geriatrics Center, University of Michigan, Ann Arbor, MI 48109-0940. Doi:10.1158/0008-5472.CAN-06-1547 mechanisms in oncogene activation and tumor suppressor inactivation in GBM is well documented [2], very little is known about the epigenetic component of this disease. Localized hypermethylation of gene-associated CpG islands and a more extensive genome-wide reduction in 5-methylcytosine are epigenetic alterations that typify many cancers [3,4,5]

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