Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas

Felsberg, Jörg; Thon, Niklas; Eigenbrod, Sabina; Hentschel, Bettina; Sabel, Michael; Westphal, Manfred; Schackert, Gabriele; Kreth, Friedrich W.; Pietsch, Torsten; Löffler, Markus; Weller, Michael; Reifenberger, Guido; Tonn, Jörg C.

doi:10.1002/ijc.26083

Cited by 266 publications

(205 citation statements)

References 36 publications

Supporting

Mentioning

182

Contrasting

Unclassified

Order By: Relevance

“…26 Meanwhile many tools are available to increase the extent of resection while keeping the risk of new neurological deficits low.…”

Section: Glioblastoma (Who Grade Iv)mentioning

confidence: 99%

“…[15][16][17][18][19] The demonstration of promoter methylation of the MGMT gene assessed by methylation-specific PCR or pyrosequencing of bisulfite-modified DNA is associated with superior outcome in anaplastic glioma patients treated with radiotherapy or alkylating agent chemotherapy 19,20 and with specific benefit from temozolomide (TMZ) in glioblastoma patients. [21][22][23][24] Retesting the MGMT status at recurrence is not necessary since the methylation status remains stable, at least in glioblastoma, 25,26 …”

Section: Molecular Diagnosticsmentioning

confidence: 99%

See 1 more Smart Citation

EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma

Weller

Bent

Hopkins

et al. 2014

The Lancet Oncology

Self Cite

685

532

View full text Add to dashboard Cite

This guideline provides recommendations for diagnostic and therapeutic procedures for patients with malignant gliomas. We differentiate evidence-based standards from reasonable options or non-evidence-based measures that should no longer be considered. The recommendations herein should provide a framework and assurance for the choice of diagnostic procedures and therapeutic measures and aim to reduce complications from unnecessary treatment and cost. The guideline contributes to a critical appreciation of concurrent drugs with a focus on the controlled use of anticonvulsants and steroids. It should serve as a guideline for all professionals involved in the diagnostics and care of glioma patients and also as a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in Europe. Implementation of the recommendations summarised here will need interdisciplinary structures of care for patients with brain tumours and structured processes of diagnostic and therapeutic procedures. AF and DF report no conflicts of interest. FundingThe preparation of this guideline was not funded. The members of the task force did not receive compensation for their participation. 5 SummaryThis guideline provides recommendations for the diagnostic and therapeutic procedures for patients with malignant gliomas. It differentiates evidence-based standards from reasonable options or non-evidence-based measures that should no longer be considered. The recommendations herein shall provide a framework and assurance for the choice of diagnostic procedures and therapeutic measures and aim to reduce complications from unnecessary treatment and cost. The guideline will contribute to a critical appreciation of concurrent medications with a focus on the controlled use of anticonvulsants and steroids. It shall serve as a guideline for all professionals involved in the diagnostics and care of glioma patients and also as a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in Europe. Implementation of the recommendations summarized here will require interdisciplinary structures of care for brain tumor patients and structured processes of diagnostic and therapeutic procedures. Key wordsAnaplastic, glioma, glioblastoma, surgery, radiotherapy, temozolomide, bevacizumab Search strategy and selection criteriaThis guideline was prepared by a task force assembled by the Executive Committee of the European Association for Neuro-Oncology (EANO) in 2013. The task force was designed to represent the different disciplines involved in the diagnosis and care of malignant glioma patients as well as to reflect the multinational composition of EANO.References for this review were identified through searches of PubMed with the search terms "glioma", "anaplastic", "glioblastoma", "trial", "clinical", "radiotherapy" 6 and "chemotherapy" from January 2005 to January 2013. Articles were also identified through searches of the authors` own files. Onl...

show abstract

“…26 Meanwhile many tools are available to increase the extent of resection while keeping the risk of new neurological deficits low.…”

Section: Glioblastoma (Who Grade Iv)mentioning

confidence: 99%

Section: Molecular Diagnosticsmentioning

confidence: 99%

EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma

Weller

Bent

Hopkins

et al. 2014

The Lancet Oncology

Self Cite

685

532

View full text Add to dashboard Cite

show abstract

“…Temporal heterogeneity of MGMT methylation is conceivable; however, matched primary GBM and their recurrences have largely revealed identical MGMT status, and retesting is currently discouraged in clinical guidelines (35). Loss of chromosome 10q has also been considered a factor influencing MGMT methylation, but recent studies found no correlation between MGMT copy number and extent of methylation in GBM (32) or low-grade gliomas (36).…”

Section: Discussionmentioning

confidence: 99%

Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma

Heuling

Knab

Radke

et al. 2017

Molecular Cancer Research

View full text Add to dashboard Cite

Promoter methylation status of O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, is a critical biomarker in glioblastoma (GBM), as treatment decisions and clinical trial inclusion rely on its accurate assessment. However, interpretation of results is complicated by poor interassay reproducibility as well as a weak correlation between methylation status and expression levels of MGMT. This study systematically investigates the influence of tumor purity on tissue subjected to MGMT analysis. A quantitative, allele-specific realtime PCR (qAS-PCR) assay was developed to determine genotype and mutant allele frequency of telomerase promoter (pTERT) mutations as a direct measure of tumor purity. We studied tumor purity, pTERT mutation by Sanger sequencing, MGMT methylation by pyrosequencing, IDH1 mutation status, and clinical parameters in a cohort of high-grade gliomas (n ¼ 97). The qAS-PCR reliably predicted pTERT genotype and tumor purity compared with independent methods. Tumor purity positively and significantly correlated with the extent of methylation in MGMT methylated GBMs. Extent of MGMT methylation differed significantly with respect to pTERT mutation hotspot (C228T vs. C250T). Interestingly, frontal lobe tumors showed greater tumor purity than those in other locations. Above all, tumor purity was identified as an independent prognostic factor in GBM. In conclusion, we determined mutual associations of tumor purity with MGMT methylation and pTERT mutations and found that the extent of MGMT methylation reflects tumor purity. In turn, tumor purity is prognostic in IDH1 wild-type GBM.Implications: Tumor purity is an independent prognostic marker in glioblastoma and is associated with the extent of MGMT methylation. Mol Cancer Res; 15(5); 532-40. Ó2017 AACR.

show abstract

“…Studies evaluating MGMT promoter methylation within glioblastoma lesions as well as in paired primary and recurrent glioblastoma samples suggested that MGMT promoter methylation could be a homogeneous marker throughout malignant gliomas (48) and that most recurrent lesions retained the methylation profile from the primary lesions (49). However, considering the increasing awareness of tumor heterogeneity (50) and the positive predictive value (77%) for serum assay observed in our study, the serum methylation assay may provide a possible alternative for patients with no available tumor samples.…”

Section: Discussionmentioning

confidence: 99%

A Phase II Study of Temozolomide in Patients with Advanced Aerodigestive Tract and Colorectal Cancers and Methylation of theO6-Methylguanine-DNA Methyltransferase Promoter

Hochhauser

Glynne‐Jones

Potter

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Responses of patients with gliomas to temozolomide are determined by O 6 -methylguanine-DNA methyltransferase (MGMT) and mismatch repair (MMR) pathways. This phase II study (NCT00423150) investigated whether MGMT promoter methylation predicts response in patients with advanced aerodigestive tract and colorectal cancers (CRC). Tumor and serum samples were screened for MGMT promoter methylation. In methylation-positive patients, 150 mg/m 2 temozolomide was administered daily on a seven-day-on, sevenday-off schedule for each 28-day cycle. The primary efficacy endpoint was response rate (RR). MMR status was determined by a microsatellite instability assay. Among 740 patients screened, 86 were positive for MGMT promoter methylation and enrolled. Nineteen percent of the screened population (137/740) had confirmed tissue and/or serum MGMT promoter methylation, including 25% (57 of 229) for CRC, 36% (55 of 154) for esophageal cancer, 11% (12 of 113) for head and neck cancer, and 5% (13 of 242) for non-small cell lung carcinoma. Among patients with valid methylation results in both tissue and serum samples, concordance was 81% (339 of 419). The majority of enrolled patients (69 of 86; 80%) had microsatellite stable cancer. Overall RR was 6% (5 of 86 partial responses); all responders had microsatellite stable cancer. Temozolomide resulted in low RRs in patients enriched for MGMT methylation. MGMT methylation status varied considerably in the patient population. Although serum methylation assay is an option for promoter methylation detection, tissue assay remains the standard for methylation detection. The low RR of this cohort of patients indicates that MGMT methylation as a biomarker is not applicable to heterogeneous tumor types, and tumor-specific factors may override validated biomarkers. Mol Cancer Ther; 12(5); 809-18. Ó2013 AACR.

show abstract

Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas

Cited by 266 publications

References 36 publications

EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma

EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma

Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma

A Phase II Study of Temozolomide in Patients with Advanced Aerodigestive Tract and Colorectal Cancers and Methylation of theO6-Methylguanine-DNA Methyltransferase Promoter

Contact Info

Product

Resources

About