MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status

Bady, Pierre; Sciuscio, Davide; Diserens, Annie Claire; Bloch, Jocelyne; Bent, Martin J. van den; Marosi, Christine; Dietrich, Pierre Yves; Weller, Michael; Mariani, Luigi; Heppner, Frank L.; McDonald, David; Lacombe, Denis; Stupp, Roger; Delorenzi, Mauro; Hegi, Monika E.

doi:10.1007/s00401-012-1016-2

Cited by 288 publications

(289 citation statements)

References 49 publications

Supporting

Mentioning

278

Contrasting

Unclassified

Order By: Relevance

“…For the detection of amplifications and chromosomal gains and losses, automatic scoring was verified by manual assessment of the respective loci for each individual profile [10,19]. The MGMT promoter methylation status and the presence of the glioma CpG island methylator phenotype (CIMP) were determined based on 450k array data [1,24].…”

Section: Patients and Neuroimagingmentioning

confidence: 99%

Gliomatosis cerebri: no evidence for a separate brain tumor entity

et al. 2015

Self Cite

View full text Add to dashboard Cite

Gliomatosis cerebri (GC) is presently considered a distinct astrocytic glioma entity according to the WHO classification for CNS tumors. It is characterized by widespread, typically bilateral infiltration of the brain involving three or more lobes. Genetic studies of GC have to date been restricted to the analysis of individual glioma-associated genes, which revealed mutations in the isocitrate dehydrogenase 1 (IDH1) and tumor protein p53 (TP53) genes in subsets of patients. Here, we report on a genome-wide analysis of DNA methylation and copy number aberrations in 25 GC patients. Results were compared with those obtained for 105 patients with various types of conventional, i.e., non-GC gliomas including diffuse astrocytic gliomas, oligodendrogliomas and glioblastomas. In addition, we assessed the prognostic role of methylation profiles and recurrent DNA copy number aberrations in GC patients. Our data reveal that the methylation profiles in 23 of the 25 GC tumors corresponded to either IDH mutant astrocytoma (n = 6), IDH mutant and 1p/19q codeleted oligodendroglioma (n = 5), or IDH wild-type glioblastoma including various molecular subgroups, i.e., H3F3A-G34 mutant (n = 1), receptor tyrosine kinase 1 (RTK1, n = 4), receptor tyrosine kinase 2 (classic) (RTK2, n = 2) or mesenchymal (n = 5) glioblastoma groups. Two tumors showed methylation profiles of normal brain tissue due to low tumor cell content. While histological grading (WHO grade IV vs. WHO grade II and III) was not prognostic, the molecular classification as classic/RTK2 or mesenchymal glioblastoma was associated with worse overall survival. Multivariate Cox regression analysis revealed MGMT promoter methylation as a positive prognostic factor. Taken together, DNA-based large-scale molecular profiling indicates that GC comprises a genetically and epigenetically heterogeneous group of diffuse gliomas that carry DNA methylation and copy number profiles closely matching the common molecularly defined glioma entities. These data support the removal of GC as a distinct glioma entity in the upcoming revision of the WHO classification. 3

show abstract

Section: Patients and Neuroimagingmentioning

confidence: 99%

Gliomatosis cerebri: no evidence for a separate brain tumor entity

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…The EORTC 26951 also provides evidence for this interaction, but case numbers available to tackle that question were not sufficient. In addition, this trial also showed that MGMT methylation, here determined using 450 k data and the MGMT-STP27 model [78], which associated methylation at two particular CpG (Fig. 1), is of utmost relevance for the prediction of the effect of the procarbazine/lomustine/vincristine (PCV), also mainly alkylating and methylating chemotherapy [103] (Fig.…”

Section: Interdependence Of Mgmt Promoter Methylation and Idh1/2 Mutamentioning

confidence: 84%

“…Although MSP has evolved as the 'most commonly applied standard' due to its simplicity and cost effectiveness, it has the disadvantage that it cannot detect heterogeneous patterns of methylation [82], especially when performed on low quality DNA extracted from FFPE tissue [78,83] (Fig. 4).…”

Section: Towards Standardized Testing For Diagnostic Assessment Of Thmentioning

confidence: 99%

MGMT testing—the challenges for biomarker-based glioma treatment

et al. 2014

Self Cite

View full text Add to dashboard Cite

Many patients with malignant gliomas do not respond to alkylating agent chemotherapy. Alkylator resistance of glioma cells is mainly mediated by the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT). Epigenetic silencing of the MGMT gene by promoter methylation in glioma cells compromises this DNA repair mechanism and increases chemosensitivity. MGMT promoter methylation is, therefore, a strong prognostic biomarker in paediatric and adult patients with glioblastoma treated with temozolomide. Notably, elderly patients (>65-70 years) with glioblastoma whose tumours lack MGMT promoter methylation derive minimal benefit from such chemotherapy. Thus, MGMT promoter methylation status has become a frequently requested laboratory test in neuro-oncology. This Review presents current data on the prognostic and predictive relevance of MGMT testing, discusses clinical trials that have used MGMT status to select participants, evaluates known issues concerning the molecular testing procedure, and addresses the necessity for molecular-context-dependent interpretation of MGMT test results. Whether MGMT promoter methylation testing should be offered to all individuals with glioblastoma, or only to elderly patients and those in clinical trials, is also discussed. Justifications for withholding alkylating agent chemotherapy in patients with MGMT-unmethylated glioblastomas outside clinical trials, and the potential role for MGMT testing in other gliomas, are also discussed. What is the role for MGMT testing in other gliomas? The answers to these issues depend not only on data from controlled clinical trials, but also on the availability of alternative treatment options to alkylating agents treatment, as well as on the access to molecular testing and its sensitivity and specificity.

show abstract

“…Because most IDH1/2-mutant tumors exhibit MGMT promoter methylation, an independent association of MGMT promoter methylation with outcome cannot be assessed in this cohort. The frequent MGMT promoter methylation in IDH1/2 mutant glioblastomas suggests that MGMT belongs to the G-CIMP gene set (23). This association may explain why MGMT promoter methylation in patients with anaplastic gliomas, tumors with a high frequency of IDH1/2 mutations, confers a prognostic benefit independent of the therapy regime (24,25).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

Hartmann¹,

Hentschel

Simon

et al. 2013

Clinical Cancer Research

Self Cite

175

108

View full text Add to dashboard Cite

Purpose: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in World Health Organization (WHO) grades II and III gliomas, but rare in primary glioblastomas, and associated with longer survival.Experimental Design: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival >36 months (LTS-36), including 33 patients surviving >60 months (LTS-60), with 257 patients surviving <36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations, and IDH1/2 mutations were determined by standard techniques.Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23 of 67 patients) as opposed to 4.3% in controls (11 of 257 patients). Long-term survivors with IDH1/2-mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Long-term survivors with IDH1/2 wild-type showed no distinguishing features from other patients with IDH1/2 wild-type glioblastomas except for a higher rate of MGMT promoter methylation. Similarly, among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less-frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had less frequently TP53 mutations and radiotherapy alone as initial treatment.Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade II/III gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.

show abstract

MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status

Cited by 288 publications

References 49 publications

Gliomatosis cerebri: no evidence for a separate brain tumor entity

Gliomatosis cerebri: no evidence for a separate brain tumor entity

MGMT testing—the challenges for biomarker-based glioma treatment

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

Contact Info

Product

Resources

About