Promoter Hypermethylation of the DNA Repair Gene O⁶‐Methylguanine‐DNA Methyltransferase is an Independent Predictor of Shortened Progression Free Survival in Patients with Low‐grade Diffuse Astrocytomas

Abstract

The O6‐methylguanine‐DNA methyltransferase (MGMT) plays a major role in repairing DNA damage from alkylating agents. In several human neoplasms including low‐grade diffuse astrocytomas, promoter hypermethylation of MGMT has been shown to correlate with an increased frequency of p53 mutation. In the present study, we analyzed MGMT promoter methylation by the methylation‐specific PCR in 49 newly diagnosed WHO grade II astrocytomas and evaluated its clinical usefulness. MGMT promoter methylation was found in 21 (43%) of the 49 tumors. A tight correlation existed between MGMT methylation and p53 protein accumulation (P=0.0424). The presence of MGMT methylation was significantly associated with a shorter progression free survival (PFS) on both univariate analysis (P=0.0014) and multivariate analysis (P=0.0081). It was a more powerful determinant of the PFS than age, sex, performance status, proliferative activity, or p53 expression, and was independent of the extent of surgery. In terms of the overall survival, MGMT methylation demonstrated a prognostic utility in the univariate analysis but not in the multivariate analysis. The present findings indicate that aberrant methylation of the MGMT promoter independently augurs for an unfavorable clinical course in patients with low‐grade diffuse astrocytomas. Since the presence of MGMT methylation is expected to predict an increased sensitivity to alkylating chemotherapeutic agents, earlier chemotherapy could serve to improve an unfavorable natural history in tumors with MGMT methylation.

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

“…62 The population was, however, mixed, in that approximately one-quarter of the patients were untreated after surgery, one-quarter received radiotherapy, and half received interferon only. By contrast, protracted treatment with temozolomide in a phase II study in low-grade glioma showed improved outcome in patients with MGMT promoter methylation.…”

“…A study of 14 patients with initial low-grade astrocytoma histology showed that three patients acquired methylation at recurrence, but no initially methylated tumor lost its methylation. 62 Another small study reported changes in methylation status in three of ten patients, but a possible relationship with treatment was not explored. 70 Of ten patients treated with temozolomide chemoradiation in phase II or III trials, 11 Europe at least, withholding temozolomide from patients with newly diagnosed glioblastoma without MGMT promoter methylation is considered to be justified in the context of clinical trials to test the effect of a new compound.…”

Preliminary Individualized Chemotherapy for Malignant Astrocytomas Based on O6-Methylguanine-Deoxyribonucleic Acid Methyltransferase Methylation Analysis

“…6) PCR was carried out as described previously. 13,24) Amplified products were electrophoresed on 3% agarose gels, and were visualized with ethidium bromide. CpGenome Universal Methylated DNA (Intergen) and normal blood DNA were included in each PCR experiment as methylated and unmethylated controls, respectively.…”

Genomic Abnormalities in Gliomas

“…Because of its critical role in DNA repair, the epigenetic silencing of MGMT is associated with an increased number of mutations and with a poorer outcome in glioblastomas. Thus, MGMT silencing is considered to be a biomarker for poor prognosis (Komine et al, 2003). However, an association between MGMT promoter methylation and the response of malignant gliomas to alkylating chemotherapy using nitrosourea compounds, temozolomide, or a combination of both has been observed (Esteller et al, 2000;Herrlinger et al, 2006).…”

“…Rivera et al (2010) recently reported that MGMT promoter methylation in anaplastic gliomas (WHO grade III) is also predictive of the response to radiotherapy and linked to longer survival in the absence of adjuvant chemotherapy. The use of temozolomide based on MGMT methylation status highlights the importance of understanding epigenetic changes in glioblastomas for the discovery of novel therapies and prognostic factors for the treatment of this deadly cancer (Komine et al, 2003;Nakagawachi et al, 2003) …”