scholarly journals Identifying the optimal cutoff point for MGMT promoter methylation status in glioblastoma

CNS Oncology ◽  
2021 ◽  
pp. CNS74
Author(s):  
Ngan Nguyen ◽  
Jordan Redfield ◽  
Matthew Ballo ◽  
Madison Michael ◽  
Jeffrey Sorenson ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Roc Analysis ◽  
Methylation Status ◽  
Cutoff Point ◽  
Mgmt Methylation ◽  
Optimal Cutoff ◽  
Methylguanine Dna Methyltransferase ◽  
Risk Of Death ◽  
Crude Model ◽  
Optimal Cutoff Point

Aim: To define the optimal cutoff point for determining methylation status of O6-methylguanine-DNA methyltransferase (MGMT) by pyrosequencing in glioblastoma. Patients & methods: A retrospective study of 109 glioblastoma patients was performed to determine the optimal cutoff point for MGMT methylation status. Results: Receiver operating characteristic (ROC) analysis revealed 21% as the optimal cutoff (sensitivity: 68%; specificity: 59%) for MGMT methylation corresponding with the highest likelihood ratio of 1.66 and accuracy of 0.65. Methylation status (hazard ratio: 0.453; 95% CI: 0.279–0.735; p = 0.001) was associated with better overall survival. The crude model indicated linearity between methylation percent and survival rate; an increase of 10% of methylation resulted in a reduction of risk of death by 20% (p = 0.004). Conclusion: ROC analysis determined 21% as the optimal cutoff point for MGMT methylation status by pyrosequencing.

scholarly journals Do we really know who has an MGMT methylated glioma? Results of an international survey regarding use of MGMT analyses for glioma

2019 ◽  
Vol 7 (1) ◽  
pp. 68-76 ◽  
Author(s):  
Annika Malmström ◽  
Małgorzata Łysiak ◽  
Bjarne Winther Kristensen ◽  
Elizabeth Hovey ◽  
Roger Henriksson ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Clinical Decision Making ◽  
Methylation Status ◽  
Clinical Decision ◽  
International Survey ◽  
Mgmt Methylation ◽  
International Consensus ◽  
Methylguanine Dna Methyltransferase ◽  
Cpg Sites ◽  
International Consensus Guidelines

Abstract Background Glioma O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status informs clinical decision making. Worldwide different methods and cutoff levels are used, which can lead to discordant methylation results. Methods We conducted an international survey to clarify which methods are regularly used and why. We also explored opinions regarding international consensus on methods and cutoff. Results The survey had 152 respondents from 25 countries. MGMT methylation status is determined for all glioblastomas in 37% of laboratories. The most common methods are methylation-specific polymerase chain reaction (msPCR) (37%) and pyrosequencing (34%). A method is selected for simplicity (56%), cost-effectiveness (50%), and reproducibility of results (52%). For sequencing, the number of CpG sites analyzed varies from 1–3 up to more than 16. For 50% of laboratories, the company producing the kit determines which CpG sites are examined, whereas 33% select the sites themselves. Selection of cutoff is equally distributed among a cutoff defined in the literature, by the local laboratory, or by the outside laboratory performing the analysis. This cutoff varies, reported from 1% to 30%, and in 1 laboratory tumor is determined as methylated in case of 1 methylated CpG site of 17 analyzed. Some report tumors as unmethylated or weakly vs highly methylated. An international consensus on MGMT methylation method and cutoff is warranted by 66% and 76% of respondents, respectively. The method preferred would be msPCR (45%) or pyrosequencing (42%), whereas 18% suggest next-generation sequencing. Conclusion Although analysis of MGMT methylation status is routine, there is controversy regarding laboratory methods and cutoff level. Most respondents favor development of international consensus guidelines.

scholarly journals Tim-3 protein expression with MGMT methylation status in glioblastoma and association with survival

2020 ◽  
Author(s):  
ji zhang ◽  
Xiaoli Wang ◽  
Shengquan Ye ◽  
Lijiao Liang ◽  
Yi Zhou ◽  
...  
Keyword(s):  
Protein Expression ◽  
Promoter Methylation ◽  
Immune Checkpoint ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Prognostic Significance ◽  
Mgmt Promoter Methylation ◽  
Mgmt Methylation ◽  
Methylguanine Dna Methyltransferase ◽  
Mgmt Promoter

Abstract Background Understanding the molecular landscape of glioblastoma (GBM) is increasingly crucial for its therapy. Immune checkpoint molecules motivated the emergence of immune checkpoint-targeting therapeutic strategies. However, the prognostic significance of the immune checkpoint molecule T cell immunoglobulin mucin-3 (Tim-3) on tumor-infiltrating immune cells (TIICs) and O-6-Methylguanine-DNA methyltransferase (MGMT) methylation status remains to be fully elucidated. We aimed to develop an MGMT methylation status-associated immune prognostic signature for predicting prognosis in GBMs.Patients and Methods: A total of 84 patients with newly diagnosed GBM were involved. MGMT methylation status was retrospectively analyzed and the expression level of Tim-3 protein was investigated using immunohistochemistry (IHC). The correlation between Tim-3 protein expression and MGMT methylation status, and the prognosis was explored.Results The obtained data showed that Tim-3 protein was expressed at different levels in GBMs. Mesenchymal expression of Tim-3 protein in these tissues was 73.81% (62/84), including low 15.48% (13/84), moderate 7.14% (6/84) and strong expression 51.19% (43/84), respectively. Of the 48 patients whose tumors tested positive for MGMT methylation, the remaining 36 patients was negative.Conclusions We profiled the immune status in GBM with MGMT promoter methylation and established a local immune signature for GBM, which could independently identify patients with a favorable prognosis, indicating the relationship between prognosis and immune. MGMT promoter methylation with lower Tim-3 protein expression was statistically significantly associated with better survival.

scholarly journals Evaluation of MGMT gene methylation in neuroendocrine neoplasms

2021 ◽  
Author(s):  
Rosa Della Monica ◽  
Mariella Cuomo ◽  
Roberta Visconti ◽  
Annabella di Mauro ◽  
Michela Buonaiuto ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Alkylating Agents ◽  
Methylation Status ◽  
Neuroendocrine Neoplasms ◽  
Mgmt Methylation ◽  
Gene Methylation ◽  
Mgmt Gene ◽  
Methylguanine Dna Methyltransferase ◽  
Specific Pcr ◽  
Well Differentiated

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O-6-methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high resolution next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in well-differentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs

scholarly journals Glioblastoma Recurrence and the Role of O6-Methylguanine–DNA Methyltransferase Promoter Methylation

2019 ◽  
pp. 1-12 ◽  
Author(s):  
Katie Storey ◽  
Kevin Leder ◽  
Andrea Hawkins-Daarud ◽  
Kristin Swanson ◽  
Atique U. Ahmed ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Inhibitory Effect ◽  
Mgmt Methylation ◽  
Repair Gene ◽  
Methylguanine Dna Methyltransferase ◽  
Downward Shift ◽  
Dna Repair Gene

Tumor recurrence in glioblastoma multiforme (GBM) is often attributed to acquired resistance to the standard chemotherapeutic agent, temozolomide (TMZ). Promoter methylation of the DNA repair gene MGMT (O6-methylguanine–DNA methyltransferase) has been associated with sensitivity to TMZ, whereas increased expression of MGMT has been associated with TMZ resistance. Clinical studies have observed a downward shift in MGMT methylation percentage from primary to recurrent stage tumors; however, the evolutionary processes that drive this shift and more generally the emergence and growth of TMZ-resistant tumor subpopulations are still poorly understood. Here, we develop a mathematical model, parameterized using clinical and experimental data, to investigate the role of MGMT methylation in TMZ resistance during the standard treatment regimen for GBM—surgery, chemotherapy, and radiation. We first found that the observed downward shift in MGMT promoter methylation status between detection and recurrence cannot be explained solely by evolutionary selection. Next, our model suggests that TMZ has an inhibitory effect on maintenance methylation of MGMT after cell division. Finally, incorporating this inhibitory effect, we study the optimal number of TMZ doses per adjuvant cycle for patients with GBM with high and low levels of MGMT methylation at diagnosis.

scholarly journals Methylation of MGMT promoter does not predict response to temozolomide in patients with glioblastoma in Donostia Hospital

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Larraitz Egaña ◽  
Jaione Auzmendi-Iriarte ◽  
Joaquin Andermatten ◽  
Jorge Villanua ◽  
Irune Ruiz ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Progression Free Survival ◽  
Mgmt Promoter Methylation ◽  
Mgmt Methylation ◽  
Free Survival ◽  
Methylguanine Dna Methyltransferase ◽  
Mgmt Promoter ◽  
Newly Diagnosed Glioblastoma

Abstract O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status has been considered a prognostic factor in newly diagnosed glioblastoma (GBM). In this study, we evaluated the prognostic and predictive value of MGMT promoter methylation in patients with glioblastoma in Donostia Hospital. Surprisingly, methylation of MGMT promoter did not predict response to temozolomide in patients with glioblastoma in Donostia Hospital. Specifically, overall survival (OS) and progression-free survival (PFS) did not differ significantly by MGMT methylation status in our cohort. In contrast, both were longer in patients who received treatment, received more TMZ cycles, had a better general status and perform at least a partial resection. No association was detected between methylation of MGMT promoter and molecular markers such as ATRX, IDH, p53 and Ki67. These results indicate that MGMT methylation did not influence in patient survival in our cohort.

scholarly journals A quantitative framework for modeling COVID-19 risk during adjuvant therapy using published randomized trials of glioblastoma in the elderly

2020 ◽  
Vol 22 (7) ◽  
pp. 918-927 ◽  
Author(s):  
Shervin Tabrizi ◽  
Lorenzo Trippa ◽  
Daniel Cagney ◽  
Shyam Tanguturi ◽  
Steffen Ventz ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Randomized Trials ◽  
Methylation Status ◽  
The Elderly ◽  
Mgmt Methylation ◽  
Individual Patient Level ◽  
Methylguanine Dna Methyltransferase ◽  
Treatment Regimens ◽  
Kaplan Meier ◽  
Medium Risk

Abstract Background During the ongoing COVID-19 pandemic, contact with the health care system for cancer treatment can increase risk of infection and associated mortality. Treatment recommendations must consider this risk for elderly and vulnerable cancer patients. We reanalyzed trials in elderly glioblastoma (GBM) patients, incorporating COVID-19 risk, in order to provide a quantitative framework for comparing different radiation (RT) fractionation schedules on patient outcomes. Methods We extracted individual patient-level data for 1321 patients from Kaplan–Meier curves from 5 randomized trials on treatment of elderly GBM patients including available subanalyses based on O6-methylguanine-DNA methyltransferase (MGMT) methylation status. We simulated trial data with incorporation of COVID-19–associated mortality risk in several scenarios (low, medium, and high infection and mortality risks). Median overall survival and hazard ratios were calculated for each simulation replicate. Results Our simulations reveal how COVID-19–associated risks affect survival under different treatment regimens. Hypofractionated RT with concurrent and adjuvant temozolomide (TMZ) demonstrated the best outcomes in low and medium risk scenarios. In frail elderly patients, shorter courses of RT are preferable. In patients with methylated MGMT receiving single modality treatment, TMZ-alone treatment approaches may be an option in settings with high COVID-19–associated risk. Conclusions Incorporation of COVID-19–associated risk models into analysis of randomized trials can help guide clinical decisions during this pandemic. In elderly GBM patients, our results support prioritization of hypofractionated RT and highlight the utility of MGMT methylation status in decision making in pandemic scenarios. Our quantitative framework can serve as a model for assessing COVID-19 risk associated with treatment across neuro-oncology. Key Points • Re-analysis of randomized controlled trials in COVID-19 era gives insight on optimal treatment of GBM. • Hypofractionated RT or temozolomide alone may be reasonable options in high risk pandemic settings. • A quantitative framework incorporating COVID-19 risks can be applied across neuro-oncology.

scholarly journals Lack of Benefit of Extending Temozolomide Treatment in Patients with High Vascular Glioblastoma with Methylated MGMT

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5420
Author(s):  
María del Mar Álvarez-Torres ◽  
Elies Fuster-García ◽  
Carmen Balaña ◽  
Josep Puig ◽  
Juan M. García-Gómez
Keyword(s):  
Adjuvant Chemotherapy ◽  
Dna Methyltransferase ◽  
Cerebral Blood Volume ◽  
Methylation Status ◽  
Mgmt Methylation ◽  
Methylguanine Dna Methyltransferase ◽  
Prognostic Effect ◽  
Multicenter Cohort ◽  
Survival Difference ◽  
Different Populations

In this study, we evaluated the benefit on survival of the combination of methylation of O6-methylguanine-DNA methyltransferase (MGMT) promotor gene and moderate vascularity in glioblastoma using a retrospective dataset of 123 patients from a multicenter cohort. MRI processing and calculation of relative cerebral blood volume (rCBV), used to define moderate- and high-vascular groups, were performed with the automatic ONCOhabitats method. We assessed the previously proposed rCBV threshold (10.7) and the new calculated ones (9.1 and 9.8) to analyze the association with survival for different populations according to vascularity and MGMT methylation status. We found that patients included in the moderate-vascular group had longer survival when MGMT is methylated (significant median survival difference of 174 days, p = 0.0129*). However, we did not find significant differences depending on the MGMT methylation status for the high-vascular group (p = 0.9119). In addition, we investigated the combined correlation of MGMT methylation status and rCBV with the prognostic effect of the number of temozolomide cycles, and only significant results were found for the moderate-vascular group. In conclusion, there is a lack of benefit of extending temozolomide treatment for patients with high vascular glioblastomas, even presenting MGMT methylation. Preliminary results suggest that patients with moderate vascularity and methylated MGMT glioblastomas would benefit more from prolonged adjuvant chemotherapy.

scholarly journals Patients Affected by Unmethylated O(6)-Methylguanine-DNA Methyltransferase Glioblastoma Undergoing Radiochemotherapy May Benefit from Moderately Dose-Escalated Radiotherapy

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Paolo Tini ◽  
Valerio Nardone ◽  
Pierpaolo Pastina ◽  
Giuseppe Battaglia ◽  
Clelia Miracco ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Methylation Status ◽  
Disease Free Survival ◽  
Newly Diagnosed ◽  
Mgmt Methylation ◽  
Free Survival ◽  
Methylguanine Dna Methyltransferase ◽  
Therapeutic Results ◽  
Newly Diagnosed Glioblastoma ◽  
Disease Free

Purpose. To compare the therapeutic results of two radiotherapy (RT) dose schedules in combined temozolomide- (TMZ-) RT treatment in newly diagnosed glioblastoma (GB), according to the O(6)-methylguanine-DNA methyltransferase (MGMT) methylation status.Material and Method. Patients received either standard (60 Gy) or moderately escalated dose (70 Gy) radiotherapy (RT) with concomitant and adjuvant TMZ between June 2006 and October 2013. We retrospectively evaluated the therapeutic effectiveness of RT schedules in terms of Overall Survival (OS) and Progression-Disease Free Survival (PDFS) analyzing the MGMT methylation status.Results. One hundred and seventeen patients were selected for the present analysis. Seventy-two out of the selected cases received the standard RT-TMZ course (SDRT-TMZ) whereas the remaining 45 underwent the escalated schedule (HDRT-TMZ). The analysis according to the MGMT promoter methylation status showed that, in unmethylated-MGMT GB patients, HDRT-TMZ and SDRT-TMZ groups had different median OS (p=0,01) and PDFS (p=0,007), that is, 8 months and 5 months for the SDRT-TMZ group and 14 months and 9 months for the HDRT-TMZ group, respectively. No difference in survival outcomes was found in methylated MGMT patients according to the two RT schedules (p=0,12).Conclusions. In our experience, unmethylated-MGMT GB patients benefited from a moderately escalated dose of RT plus TMZ.

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