Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome

Jan 19, 2013Neuro-oncology

Using DNA repair protein levels and gene regulation to better predict glioblastoma outcomes

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Abstract

Patients with <30% MGMT protein expression had a progression-free survival of 10.9 months and overall survival of 20.5 months.

Patients with ≥30% MGMT protein expression had significantly longer progression-free survival of 7.8 months and overall survival of 16.7 months.
A high correlation was observed between MGMT promoter methylation status and IHC staining results.
Low IHC staining was frequently found even when promoter methylation was absent.
Increased methylation density was linked to decreased IHC staining and improved survival outcomes.
Multivariate analysis indicated that patients with both tandem promoter methylation and low MGMT expression had better overall and progression-free survival.

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BACKGROUND: Promoter methylation of the DNA repair gene, O-6-methylguanine-DNA methyltransferase (MGMT), is associated with improved treatment outcome for newly diagnosed glioblastoma (GBM) treated with standard chemoradiation. To determine the prognostic significance of MGMT protein expression as assessed by immunohistochemistry (IHC) and its relationship with methylation, we analyzed MGMT expression and promoter methylation with survival in a retrospective patient cohort.

METHODS: We identified 418 patients with newly diagnosed GBM at University of California Los Angeles Kaiser Permanente Los Angeles, nearly all of whom received chemoradiation, and determined MGMT expression by IHC, and MGMT promoter methylation by methylation-specific PCR (MSP) and bisulfite sequencing (BiSEQ) of 24 neighboring CpG sites.

RESULTS: With use of the median percentage of cells staining by IHC as the threshold, patients with <30% staining had progression-free survival (PFS) of 10.9 months and overall survival (OS) of 20.5 months, compared with PFS of 7.8 months (P < .0001) and OS of 16.7 months (P < .0001) among patients with ≥30% staining. Inter- and intrareader correlation of IHC staining was high. Promoter methylation status by MSP was correlated with IHC staining. However, low IHC staining was frequently observed in the absence of promoter methylation. Increased methylation density determined by BiSEQ correlated with both decreased IHC staining and increased survival, providing a practical semiquantitative alternative to MSP. On the basis of multivariate analysis validated by bootstrap analysis, patients with tandem promoter methylation and low expression demonstrated improved OS and PFS, compared with the other combinations.

CONCLUSIONS: Optimal assessment of MGMT status as a prognostic biomarker for patients with newly diagnosed GBM treated with chemoradiation requires determination of both promoter methylation and IHC protein expression.

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Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome

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