O 6-Methylguanine DNA Methyltransferase Gene Promoter Methylation Status in Gliomas and Its Correlation With Other Molecular Alterations: First Indian Report With Review of Challenges for Use in Customized Treatment

Nov 26, 2010Neurosurgery

Methylation of a DNA Repair Gene in Brain Tumors and Its Link to Other Molecular Changes: First Report from India and Challenges for Personalized Treatment

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Abstract

79.4% of grade II gliomas exhibited MGMT promoter methylation.

MGMT promoter methylation frequency inversely correlated with tumor grade, observed in 70.8% of grade III and 56.8% of grade IV gliomas.
A statistically significant difference in MGMT methylation was found between grade II and grade IV tumors (P=.036).
Most gliomas with 1p/19q loss of heterozygosity also showed MGMT methylation, though this association was not statistically significant.
No significant correlation was found between MGMT status and IDH1 mutation in the studied gliomas.
In astrocytic tumors, no correlation was observed between MGMT methylation and either TP53 mutation or EGFR amplification.

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BACKGROUND: O6-methylguanine methyltransferase (MGMT) promoter methylation in adult glioblastomas (glioblastoma multiforme) is considered a promising molecular alteration, predictive of better response to temozolomide therapy and longer overall survival.

OBJECTIVE: To look at the frequency of MGMT methylation in glial tumors of all grades and types, and correlate this alteration with loss of heterozygosity 1p/19q, TP53 gene mutations, epidermal growth factor receptor (EGFR) amplification, and isocitrate dehydrogenase 1 (IDH1) mutations.

METHODS: One hundred two gliomas of various grades and subtypes were assessed by methylation-specific polymerase chain reaction for MGMT promoter methylation status. The results were correlated with 1p/19q status, EGFR amplification, TP53, and IDH1 mutations.

RESULTS: There was an inverse correlation of MGMT promoter methylation frequency with tumor grade, observed in 79.4%, 70.8%, and 56.8% of grade II, grade III, and grade IV gliomas, respectively. The difference was statistically significant in grade II vs IV tumors (P=.036). The majority of cases with 1p/19q loss of heterozygosity also showed MGMT methylation, although the association was not significant. There was no significant correlation of MGMT status with IDH1 mutation. In astrocytic tumors, there was no correlation of MGMT methylation with TP53 mutation or EGFR amplification.

CONCLUSION: MGMT promoter methylation was observed in a considerable proportion of all grades and subtypes of gliomas, with no significant correlation with other known genetic alterations. On extensive literature review, in both low- and high-grade gliomas, wide variability of data on the frequency of MGMT methylation and its association with other molecular alterations from various centers was noted, mostly owing to technical causes. This raises questions regarding the capacity of this test for use as an objective and reproducible marker for customized treatment in individual cases.

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O 6-Methylguanine DNA Methyltransferase Gene Promoter Methylation Status in Gliomas and Its Correlation With Other Molecular Alterations: First Indian Report With Review of Challenges for Use in Customized Treatment

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