Evaluation of MGMT promoter methylation status and correlation with temozolomide response in orthotopic glioblastoma xenograft model

Nov 18, 2008Journal of neuro-oncology

MGMT Gene Methylation and Its Link to Temozolomide Response in Brain Tumor Models

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Abstract

MGMT promoter methylation is associated with enhanced survival in glioblastoma multiforme patients treated with temozolomide.

Approximately 50% of glioblastoma multiforme tumors show MGMT promoter methylation.
A significant inverse relationship exists between MGMT protein expression and survival benefit from temozolomide treatment (r=-0.75; P=0.003).
Temozolomide responsiveness correlates positively with MGMT promoter methylation as measured by quantitative MS-PCR (r=0.72; P=0.006).
A high methylation signal from quantitative MS-PCR corresponds to an increased number of methylated CpG sites (r=0.78, P=0.002).
Heterogeneity in CpG methylation was observed, with some tumors exhibiting unmethylated sites despite strong methylation signals.

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CpG methylation within the O6-methylguanine-DNA-methyltransferase (MGMT) promoter is associated with enhanced survival of glioblastoma multiforme (GBM) patients treated with temozolomide (TMZ). Although MGMT promoter is methylated in approximately 50% of GBM, several studies have reported a lack of correlation between MGMT methylation and protein expression levels and consequently inaccurate discrimination of TMZ sensitive and resistant patients. To understand the limitations of currently used assays, TMZ responsiveness of 13 GBM xenograft lines was correlated with MGMT protein expression and MGMT promoter methylation determined by (1) standard methylation-specific polymerase chain reaction (MS-PCR), (2) quantitative MS-PCR (qMS-PCR), and (3) bisulfite sequencing. For each xenograft line, mice with established intracranial xenografts were treated with vehicle control or TMZ (66 mg/kgx5 days), and TMZ response was defined as relative prolongation in median survival for TMZ-treated versus control-treated mice. The relative survival benefit with TMZ was inversely related to MGMT protein expression (r=-0.75; P=0.003) and directly correlated with qMS-PCR (r=0.72; P=0.006). There was a direct correlation between MGMT methylation signal by qMS-PCR and the number of methylated CpG sites within the region amplified by MS-PCR (r=0.78, P=0.002). However, bisulfite sequencing revealed heterogeneity in the extent of CpG methylation in those tumors with a robust qMS-PCR signal. Three of the 4 GBM lines with a qMS-PCR signal greater than 10% had at least 1 unmethylated CpG site, while only one line was fully methylated at all 12 CpG sites. These data highlight one potential limitation of the evaluation of MGMT methylation by MS-PCR assay and suggest that more detailed evaluation of methylation at individual CpG sites relative to TMZ response may be worth pursuing.

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Evaluation of MGMT promoter methylation status and correlation with temozolomide response in orthotopic glioblastoma xenograft model

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