Human malignant gliomas (glioblastomas and anaplastic astrocytomas) are the most frequent brain tumors and are associated with a variety of genetic alterations including retinoblastoma (RB) and p53 gene mutations, loss of interferon alpha and beta (IFNA, IFNB) genes and lack of O6-methylguanine-DNA methyltransferase (MGMT) expression.
Human brain tumors that were highly resistant to ACNU, such as glioblastoma Gbl1 and metastatic brain tumor Col1 with SD10 values (microM) of above 100, expressed markedly increased amounts of 0.95 kb MGMT mRNA.
These results suggest that loss of MGMT expression as a result of promoter methylation, which frequently occurs at an early stage in the pathway leading to secondary glioblastomas, appears to be associated with increased frequency of TP53 mutations, in particular G:C --> A:T transitions.
Using the methylation-specific polymerase chain reaction, we assayed promoter hypermethylation of the MGMT gene in tumor deoxyribonucleic acid from 116 adult patients with supratentorial high-grade astrocytic tumors (42 anaplastic astrocytomas [AAs] and 74 glioblastomas multiforme [GBMs]).
This prospective clinical trial identifies MGMT-methylation status as an independent predictor for glioblastoma patients treated with a methylating agent.
This prospective clinical trial identifies MGMT-methylation status as an independent predictor for glioblastoma patients treated with a methylating agent.
While neither MGMT methylation nor TP53 mutation had a significant effect on prognosis of the whole population, the presence of MGMT methylation emerged as a significant predictor of a longer survival when exclusively analyzing 29 patients with glioblastomas multiforme.
Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.
This suggests that, in addition to deamination of 5-methylcytosine (the best known mechanism of formation of G:C-->A:T transitions at CpG sites), involvement of alkylating agents that produce O6-methylguanine or related adducts recognized by MGMTcannot be excluded in the pathway leading to secondary glioblastomas.
The lower MGMT expression in oligodendroglial tumors compared to glioblastomas (P < 0.05), which have different chemosensitivity, suggests a possible role of MGMT in the determination of chemoresistance.
The methylation rate in LTS GBM was significantly higher (77.8% vs. 39.2%, P = 0.033) which suggests that MGMT hypermethylation is a frequent hallmark of LTS GBM and contributes to characterize this intriguing GBM subtype.
In this study, we tested the hypothesis that MGMT is regulated by p53 in astrocytic cells, the precursors of which may give rise to glioblastoma. p53 is of interest because, in addition to often being mutated in glioblastoma, inactivation sensitizes some astrocytoma cell lines to temozolomide.
Interestingly, inhibitors of DNA methylation and histone deacetylation failed to increase MGMT protein levels in the transformed astrocyte cells as well as cultured glioblastoma cell lines, whereas the treatment partially restored mRNA levels.
Intratumoral homogeneity of MGMT promoter hypermethylation as demonstrated in serial stereotactic specimens from anaplastic astrocytomas and glioblastomas.
Intratumoral homogeneity of MGMT promoter hypermethylation as demonstrated in serial stereotactic specimens from anaplastic astrocytomas and glioblastomas.
Promoter methylation of the deoxyribonucleic acid (DNA) repair gene, O(6)-methylguanine-DNA methyltransferase (MGMT), is associated with improved outcome of patients with glioblastoma multiforme and anaplastic astrocytoma treated with temozolomide (TMZ).
Taken together, our findings underline the association of glioblastoma long-term survival with prognostically favourable clinical factors, in particular young age and good initial performance score, as well as MGMT promoter hypermethylation.