O 6-Methylguanine DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression is correlated with progression-free survival in patients with glioblastoma

Sonoda, Yukihiko; Yokosawa, Michiko; Saito, Ryuta; Kanamori, Masayuki; Yamashita, Yoshihisa; Kumabe, Toshihiro; Watanabe, Mika; Tominaga, Teiji

doi:10.1007/s10147-010-0065-6

Cited by 66 publications

(38 citation statements)

References 34 publications

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“…Our data also confirm MGMT methylation as a positive prognostic factor in both IDH1 -mutated and wild-type gliomas (25), with the percentage of MGMT methylation showing a direct correlation with increasing OS (38). Increased OS in patients with MGMT methylation is attributable to a positive response to TMZ, rather than a biological effect on tumor development.…”

Section: Discussionsupporting

confidence: 80%

MGMT-Methylated Alleles Are Distributed Heterogeneously Within Glioma Samples Irrespective ofIDHStatus and Chromosome 10q Deletion

Fontana¹,

Tabano²,

Bonaparte³

et al. 2016

J Neuropathol Exp Neurol

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Several molecular markers drive diagnostic classification, prognostic stratification, and/or prediction of response to therapy in patients with gliomas. Among them, IDH gene mutations are valuable markers for defining subtypes and are strongly associated with epigenetic silencing of the methylguanine DNA methyltransferase (MGMT) gene. However, little is known about the percentage of MGMT-methylated alleles in IDH-mutated cells or the potential association between MGMT methylation and deletion of chromosome 10q, which encompasses the MGMT locus. Here, we quantitatively assessed MGMT methylation and IDH1 mutation in 208 primary glioma samples to explore possible differences associated with the IDH genotype. We also explored a potential association between MGMT methylation and loss of chromosome 10q. We observed that MGMT methylation was heterogeneously distributed within glioma samples irrespective of IDH status suggesting an incomplete overlap between IDH1-mutated and MGMT-methylated alleles and indicating a partial association between these 2 events. Moreover, loss of one MGMT allele did not affect the methylation level of the remaining allele. MGMT was methylated in about half of gliomas harboring a 10q deletion; in those cases, loss of heterozygosity might be considered a second hit leading to complete inactivation of MGMT and further contributing to tumor progression.

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Section: Discussionsupporting

confidence: 80%

MGMT-Methylated Alleles Are Distributed Heterogeneously Within Glioma Samples Irrespective ofIDHStatus and Chromosome 10q Deletion

Fontana¹,

Tabano²,

Bonaparte³

et al. 2016

J Neuropathol Exp Neurol

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“…The concept is that silencing of MGMT by promoter methylation is reflected by a loss of MGMT protein expression leading to increased sensitivity of tumours to alkylation-induced DNA damage. However, most studies comparing MGMT promoter methylation analysis with loss of MGMT protein expression as a potential surrogate marker for an inactivation of the MGMT gene described only a poor or lacking correlation [12,13,14,15,16], except for a study by Sonoda et al [17] that reported a good correlation between the two methods.…”

Section: Introductionmentioning

confidence: 99%

Prognostic and Predictive Roles of MGMT Protein Expression and Promoter Methylation in Sporadic Pancreatic Neuroendocrine Neoplasms

et al. 2014

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Background/Aims: O⁶-methylguanine-methyltransferase (MGMT) is an important enzyme of DNA repair. MGMT promoter methylation is detectable in a subset of pancreatic neuroendocrine neoplasms (pNEN). A subset of pNEN responds to the alkylating agent temozolomide (TMZ). We wanted to correlate MGMT promoter methylation with MGMT protein loss in pNEN, correlate the findings with clinico-pathological data and determine the role of MGMT to predict response to TMZ chemotherapy. Methods: We analysed a well-characterized collective of 141 resected pNEN with median follow-up of 83 months for MGMT protein expression and promoter methylation using methylation-specific PCR (MSP). A second collective of 10 metastasized, pretreated and progressive patients receiving TMZ was used to examine the predictive role of MGMT by determining protein expression and promoter methylation using primer extension-based quantitative PCR. Results: In both collectives there was no correlation between MGMT protein expression and promoter methylation. Loss of MGMT protein was associated with an adverse outcome, this prognostic value, however, was not independent from grade and stage in multivariate analysis. Promoter hypermethylation was significantly associated with response to TMZ. Conclusion: Loss of MGMT protein expression is associated with adverse outcome in a surgical series of pNET. MGMT promoter methylation could be a predictive marker for TMZ chemotherapy in pNEN, but further, favourably prospective studies will be needed to confirm this result and before this observation can influence clinical routine.

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“…28,29 For MGMT promoter methylation analysis, we performed methylationspecific PCR. 23,29,30 The chromosome copy numbers of 7p (EGFR), 9p (CDKN2A), and 10q (PTEN) were analyzed by multiplex ligation-dependent probe amplification (MLPA) using the probe mix from the SALSA MLPA Kit P105 Glioma-2 (MRC-Holland), as previously reported. …”

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confidence: 99%

The expression status of CD133 is associated with the pattern and timing of primary glioblastoma recurrence

et al. 2013

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Background. Glioblastoma carries a poor prognosis primarily because of its high rate of recurrence. The ability to predict the recurrence pattern and timing would be highly useful for determining effective treatment strategies. We examined the correlation between prognostic factors and the pattern of recurrence in patients with primary glioblastoma. In particular, we examined whether there was a correlation between the expression of CD133 and glioblastoma recurrence. Methods. We retrospectively analyzed 112 patients with primary glioblastoma. The timing and pattern (local or distant) of the initial recurrence were obtained from medical records. To identify factors predictive of recurrence, we examined CD133 expression by Western blots and immunohistochemistry, clinical (age, sex, KPS, Ki67 labeling index, surgery, ventricular entry) and genetic (IDH1, 7p, 9p, 10q, MGMT) factors. Results. Of the 112 patients, 99 suffered recurrence. The first recurrence was local in 77 patients and distant in 22 patients. Among the factors to predict the pattern of recurrence, CD133 expression was significantly higher in distant than in local recurrence. Of the factors to predict the timing of recurrence, high CD133 expression was associated with shorter time to distant recurrence in both univariate and multivariate analyses (P ¼ .0011 and P ¼ .038, respectively). Conclusions. The expression of CD133 may be a predictor of the pattern and timing of recurrence of primary glioblastoma.Keywords: glioblastoma, CD133, distant recurrence, local recurrence, stem cells. P rimary glioblastoma, classified as grade IV tumor by the World Health Organization (WHO), is the most malignant tumor of the human central nervous system.1 Despite aggressive treatment, the median survival of patients with these tumors is 12.5 -15 months.2,3 During their clinical course, almost all patients suffer a posttreatment recurrence. Therefore, to improve the prognosis, the pattern and timing of tumor recurrence must be better understood.Advances in surgical treatments such as 5-aminolevulinic acid fluorescence-guided surgery, 4 intraoperative MRI, 5 and functional mapping 6 have enabled maximal resection of these tumors without eliciting severe morbidity. Postoperative treatment with temozolomide and radiation to achieve local tumor control also improves the prognosis slightly.7 Despite good control of the initial lesion, some patients suffer tumor recurrence at a distant location. 8 -12 The reported rate of postoperative distant recurrence including dissemination ranges from 8% to 43.6%. 9,11 -13 To predict and address the clinical course of patients with glioblastoma, we must acquire a better understanding of factors involved in the pattern and timing of not only local but also distant tumor recurrence. Detailed analysis of these factors may make prophylactic treatment for recurrences possible. However, there are few studies on such clinical and molecular features.Here, we conducted a retrospective study to identify the factors associated with distant and lo...

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O 6-Methylguanine DNA methyltransferase determined by promoter hypermethylation and immunohistochemical expression is correlated with progression-free survival in patients with glioblastoma

Abstract: Low MGMT expression and MGMT promoter methylation are both predictive markers for slower tumor progression in patients with glioblastoma.

Cited by 66 publications

References 34 publications

MGMT-Methylated Alleles Are Distributed Heterogeneously Within Glioma Samples Irrespective ofIDHStatus and Chromosome 10q Deletion

MGMT-Methylated Alleles Are Distributed Heterogeneously Within Glioma Samples Irrespective ofIDHStatus and Chromosome 10q Deletion

Prognostic and Predictive Roles of MGMT Protein Expression and Promoter Methylation in Sporadic Pancreatic Neuroendocrine Neoplasms

The expression status of CD133 is associated with the pattern and timing of primary glioblastoma recurrence

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