Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation.
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.
Cadieux
Benoît
B
The Brain Tumor Research Center, Department of Neurological Surgery, University of California, San Francisco, CA 94143-0875, USA.
Ching
Tsui-Ting
TT
VandenBerg
Scott R
SR
Costello
Joseph F
JF
D044503:5-Methylcytosine / Q000032:analysis; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002455:Cell Division; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D015894:Genome, Human; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency / Q000235:genetics*; D017384:Sequence Deletion
D004273:DNA, Neoplasm; D044503:5-Methylcytosine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)