Prognostic Implications of Epidermal and Platelet-derived Growth Factor Receptor Alterations in Two Cohorts of IDHwt Glioblastoma

Abstract Background Glioblastoma remains a deadly brain cancer with dismal prognosis. Genetic alterations, including IDH mutations, 1p19q co-deletion status and MGMT promoter methylation have been proven to be prognostic and predictive to response to treatment in gliomas. In this manuscript, we aimed to correlate other mutations and genetic alterations with various clinical endpoints in patients with IDH-wild-type (IDHwt) glioblastoma. Methods We compiled a comprehensive clinically annotated database of IDHwt GBM patients treated at the Ohio State University Wexner Medical Center for whom we had mutational data through a CLIA-certified genomic laboratory. We then added data that is publicly available from Memorial Sloan Kettering Cancer Center through cBioPortal. Each of the genetic alterations (mutations, deletions and amplifications) served as a variable in univariate and multivariate Cox proportional hazard models. Results A total of 175 IDHwt GBM patients with available MGMT promoter methylation data from both cohorts were included in the analysis. As expected, MGMT promoter methylation was significantly associated with improved overall survival (OS). Median OS for MGMT promoter methylated and unmethylated GBM was 26.5 and 18 months, respectively (HR 0.45; p=0.003). Moreover, EGFR/ERBB alterations were associated with favorable outcome (HR of 0.37 (p=0.003), but only in MGMT promoter unmethylated GBM. We further found that patients with EGFR/ERBB alterations who also harbored PDGFRA amplification had a significantly worse outcome (HR 7.89; p=0.025). Conclusions Our data provides further insight into the impact of genetic alterations on various clinical outcomes in IDHwt GBM in two cohorts of patients with detailed clinical information and inspire new therapeutic strategies for IDHwt GBM.

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Combinational analysis of IDH1/IDH2 mutations, 1p/19q deletions and MGMT promoter methylation for molecular testing of glioma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e13152 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e13152-e13152

Author(s):

Xiaoni Zhang ◽

Hongyue Qu ◽

Qing Yang ◽

Ziyang Zhu ◽

Tanxiao Huang ◽

...

Keyword(s):

Promoter Methylation ◽

Genetic Alterations ◽

Mgmt Promoter Methylation ◽

Molecular Testing ◽

Sequencing Data ◽

Diagnosis And Prognosis ◽

Mgmt Promoter ◽

Ffpe Samples ◽

Combinational Analysis ◽

Idh2 Mutation

e13152 Background: Mutations in IDH1 and IDH2, co-deletion of 1p and 19q, and the hyper methylation of the MGMT promoter are the most reported genetic alterations in glioma tumors. Therefore, we designed a study to analyze the prevalence of these biomarkers in glioma, and the correlation of these biomarkers with diagnosis and prognosis. Methods: From September 2018 to January 2019, eighteen patients with primary glioma were prospectively enrolled. For each patient, freshly frozen tissue or FFPE samples were collected. DNA was extracted from these samples and sequenced to at least 5,000× coverage. IDH1/IDH2 mutations and 1p/19q deletions were detected from the sequencing data, whereas MGMT promoter methylation was evaluated by real-time fluorescence qPCR. Results: Of the eighteen patients, 44.4%(8/18) and 33.3%(6/18) harbored IDH1 /IDH2 mutations and 1p/19q deletions, respectively, and 72.2%(13/18) contained MGMT promoter hyper methylation. Within these patients, we found a correlation between IDH1/IDH2 mutation and 1p/19q deletion. Namely, among the 8 patients with a IDH1/IDH2 mutation, 75%(6/8) also contained a 1p/19q deletion, whereas none of the 10 patients with wide-type IDH1/IDH2 displayed the 1p/19q deletion. There was also a correlation between mutations at the loci and MGMT promoter hyper-methylation, specifically, 87.5%(7/8) of the patients with IDH1/IDH2 mutations also exhibited hyper-methylation in MGMT, whereas only hyper-methylation was observed in only 40% (4/10) of IDH1/IDH2 negative patients. Conclusions: From our preliminary result, IDH1/IDH2 mutations may be associated with 1p/19q deletion. To further verify this result, a larger, longitudinal study is ongoing at our institution.

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Correlation of the quantitative level of MGMT promoter methylation and overall survival in primary diagnosed glioblastomas using the quantitative MethyQESD method

Journal of Clinical Pathology ◽

10.1136/jclinpath-2019-206104 ◽

2019 ◽

Vol 73 (2) ◽

pp. 112-115 ◽

Cited By ~ 2

Author(s):

Charlotte von Rosenstiel ◽

Benedikt Wiestler ◽

Bernhard Haller ◽

Friederike Schmidt-Graf ◽

Jens Gempt ◽

...

Keyword(s):

Overall Survival ◽

Promoter Methylation ◽

Promoter Region ◽

Dna Methyltransferase ◽

Methylation Status ◽

Mgmt Promoter Methylation ◽

Newly Diagnosed ◽

Quantitative Level ◽

Mgmt Promoter ◽

The Impact

AimsO(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation is a high predictive factor for therapy results of temozolomide in patients with glioma. The objective of this work was to analyse the impact of MGMT promoter methylation in patients with primary diagnosed glioblastoma (GBM) relating to survival using a quantitative method (methylation quantification of endonuclease-resistant DNA, MethyQESD) by verifying a cut-off point for MGMT methylation provided by the literature (</≥10%) and calculating an optimal cut-off.Methods67 patients aged 70 years or younger, operated between January 2013 and December 2015, with newly diagnosed IDH wild-type GBM and clinical follow-up were retrospectively investigated in this study. A known MGMT promoter methylation status was the inclusion criteria.ResultsMedian overall survival (OS) was 16.9 months. Patients who had a methylated MGMT promoter region of ≥10% had an improved OS compared with patients with a methylated promoter region of <10% (p=0.002). Optimal cut-off point for MGMT promoter methylation was 11.7% (p=0.012).ConclusionThe results confirm that the quantitative level of MGMT promoter methylation is a positive prognostic factor in newly diagnosed patients with GBM. The cut-off provided by the literature (</≥10%) and the calculated optimal cut-off value of 11.7% give a statistically significant separation. Hence, MethyQESD is a reliable method to calculate MGMT promoter methylation in GBM.

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O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and relation to 1p/19q loss in low grade gliomas: A GICNO study

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.20064 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 20064-20064 ◽

Cited By ~ 1

Author(s):

L. Nicolardi ◽

R. Bertorelle ◽

L. Bonaldi ◽

A. Compostella ◽

A. Roma ◽

...

Keyword(s):

Promoter Methylation ◽

Dna Methyltransferase ◽

Alkylating Agents ◽

Methylation Status ◽

Mgmt Promoter Methylation ◽

Low Grade ◽

Tumor Localization ◽

Response To Chemotherapy ◽

Mgmt Promoter ◽

The Impact

20064 Background: 1p and 19q deletions have been associated with a favorable response to chemotherapy and a good prognosis in patients (pts) with oligodendroglioma. MGMT promoter methylation has been associated with a longer survival in pts with glioblastoma who receive alkylating agents. As yet, there are no data on the expression of MGMT, and on the relationship between 1p/19q deletions and MGMT promoter methylation in low grade glioma (LGG). Methods: Pts that received a first line chemotherapy regimen with temozolomide for progressive LGG were enrolled in the study, designed to investigate the correlation between MGMT methylation status and 1p/19q deletions in this setting. 1p/19q deletions were analysed by FISH, and MGMT promoter methylation by methylation specific PCR (MSP). Results: Seventy-five pts (26 females, 49 males; median age 42 years: range 22–68 years) were accrued. Of these, 48 (64%) had oligodendrogliomas (O), 19 (25.3%) astrocytomas (A), and 8 (10.6%) oligoastrocytomas (OA); 44 (58.7%) had a history of epilepsy, 41 (54.7%) had a frontal tumor localization, 27 (36%) had MRI contrast enhancing lesions, and 35 (46.7%) had been pre-treated with radiotherapy. 1p/19q deletions, evaluable in 58 pts (77.3%), were both present in 36 pts (62%), (3 being A and 2 OA); 18 pts (31%) had no loss; 1 pt (1.7%) had 1p loss; 3 pts (5.2%) 19q loss. Combined 1p and 19q loss was not correlated with a frontal localization (p = 0.12), median age (0.47) and/or gender (0.62). MGMT promoter methylation, present in 17 (56.6%) of 30 assessable cases, was significantly associated with combined 1p/19q deletions (p = 0.03). MGMT promoter methylation was not significantly associated with age (p = 0.46), gender (p = 0.2), tumor localization (p = 0.12) and/or histology (0.37). Conclusions: 1p/19q deletions are strictly correlated to histology and to MGMT promoter methylation; further prospective trials are required to clarify the impact of these molecular signatures on clinical outcome. No significant financial relationships to disclose.

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Molecular Predictors of Progression-Free and Overall Survival in Patients With Newly Diagnosed Glioblastoma: A Prospective Translational Study of the German Glioma Network

Journal of Clinical Oncology ◽

10.1200/jco.2009.23.0805 ◽

2009 ◽

Vol 27 (34) ◽

pp. 5743-5750 ◽

Cited By ~ 390

Author(s):

Michael Weller ◽

Jörg Felsberg ◽

Christian Hartmann ◽

Hilmar Berger ◽

Joachim P. Steinbach ◽

...

Keyword(s):

Overall Survival ◽

Promoter Methylation ◽

Genetic Alterations ◽

Mgmt Promoter Methylation ◽

Response To Therapy ◽

Standards Of Care ◽

Isocitrate Dehydrogenase 1 ◽

Mutational Status ◽

Mgmt Promoter ◽

Idh1 Mutations

Purpose The prognostic value of genetic alterations characteristic of glioblastoma in patients treated according to present standards of care is unclear. Patients and Methods Three hundred one patients with glioblastoma were prospectively recruited between October 2004 and December 2006 at the clinical centers of the German Glioma Network. Two hundred fifty-eight patients had radiotherapy, 199 patients had temozolomide, 189 had both, and seven had another chemotherapy as the initial treatment. The tumors were investigated for TP53 mutation, p53 immunoreactivity, epidermal growth factor receptor, cyclin-dependent kinase CDK 4 or murine double minute 2 amplification, CDKN2A homozygous deletion, allelic losses on chromosome arms 1p, 9p, 10q, and 19q, O6-methylguanine methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutations. Results Median progression-free (PFS) and overall survival (OS) were 6.8 and 12.5 months. Multivariate analysis revealed younger age, higher performance score, MGMT promoter methylation, and temozolomide radiochemotherapy as independent factors associated with longer OS. MGMT promoter methylation was associated with longer PFS (relative risk [RR], 0.5; 95% CI, 0.38 to 0.68; P < .001) and OS (RR, 0.39; 95% CI, 0.28 to 0.54; P < .001) in patients receiving temozolomide. IDH1 mutations were associated with prolonged PFS (RR, 0.42; 95% CI, 0.19 to 0.91; P = .028) and a trend for prolonged OS (RR, 0.43; 95% CI, 0.15 to 1.19; P = .10). No other molecular factor was associated with outcome. Conclusion Molecular changes associated with gliomagenesis do not predict response to therapy in glioblastoma patients managed according to current standards of care. MGMT promoter methylation and IDH1 mutational status allow for stratification into prognostically distinct subgroups.

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“Long extended” temozolomide in a selected population with not radically resected high-grade gliomas.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e12510 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e12510-e12510

Author(s):

Gian Paolo Spinelli ◽

Giuseppe Lo Russo ◽

Evelina Miele ◽

Antonio Maria Alberti ◽

Martina Strudel ◽

...

Keyword(s):

Promoter Methylation ◽

Methylation Status ◽

Haematological Toxicity ◽

Mgmt Promoter Methylation ◽

Response To Treatment ◽

High Grade ◽

Number Of Patients ◽

Mgmt Promoter ◽

High Grade Gliomas ◽

Ecog Ps

e12510 Background: Despite the important progress in the treatment of solid tumors, high grade gliomas (HGGs) remain neoplasm with poor prognosis, especially when are not radically resected. Here we report the results of a selected population treated with standard schedule of Radiotherapy (RT) + Temozolomide (TMZ) followed by TMZ until progression. Methods: From January 2008 to January 2010, 14 newly diagnosed HGG patients, with median age of 50.6 years (range 27-75 yrs), were enrolled at Oncology Unit of S. Maria Goretti Hospital in Latina (University of Rome “Sapienza”). All patients were not radically resected and with ECOG PS=O. Furthermore patients were selected according to O6 Methyl-Guanine-DNA-Methyl Transferase (MGMT) promoter methylation status. Only methylated patients were included in our study. After surgery, patients received standard treatment with TMZ (75 mg/m2) concomitant with RT (60 Gy total dose). After a break of six weeks, Magnetic Resonance Imaging (MRI) was performed and all patients with stable or responsive disease received TMZ (150mg/200mg/m2/d x 5dq 28d) until progression. The response to treatment was evaluated according to RANO criteria Results: In our study the results showed one year overall survival (OS) and progression free survival (PFS) rates of 85,7% and 71,4% respectively. Moreover we observed two years OS rate of 70% and two years PFS rate of 10%. A total of 108 cycles of adjuvant TMZ were administered with average number of 9 per patient (range 1-16). The most frequent side effects observed were haematological toxicity and fatigue. Thrombocytopenia (G2-G3) was observed in 42% of patients, neutropenia (G2-G3), fatigue (G2-G3) and nausea (G2-G3) in 30%, 32% and 25% of patients respectively. Conclusions: Despite the small number of patients, our experience suggests a manageable safety profile and a good efficacy of TMZ until progression in a selected population of patients (HGGs not radically resected, with a good ECOG PS). These data also confirms the literature knowledge, underlining the prognostic positive impact of MGMT promoter methylation in patients with HGG.

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The Impact of MGMT Promoter Methylation and Temozolomide Treatment in Serbian Patients with Primary Glioblastoma

Medicina ◽

10.3390/medicina55020034 ◽

2019 ◽

Vol 55 (2) ◽

pp. 34

Author(s):

Nikola Jovanović ◽

Tatjana Mitrović ◽

Vladimir J. Cvetković ◽

Svetlana Tošić ◽

Jelena Vitorović ◽

...

Keyword(s):

Overall Survival ◽

Promoter Methylation ◽

Prognostic Value ◽

Methylation Status ◽

Promoter Hypermethylation ◽

Mgmt Promoter Methylation ◽

Mgmt Methylation ◽

Primary Glioblastoma ◽

Mgmt Promoter ◽

The Impact

Background and objective: Despite recent advances in treatment, glioblastoma (GBM) remains the most lethal and aggressive brain tumor. A continuous search for a reliable molecular marker establishes the methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter as a key prognostic factor in primary glioblastoma. The aim of our study was to screen Serbian patients with primary glioblastoma for an MGMT promoter hypermethylation and to evaluate its associations with overall survival (OS) and sensitivity to temozolomide (TMZ) treatment. Materials and methods: A cohort of 30 Serbian primary glioblastoma patients treated with radiation therapy and chemotherapy were analyzed for MGMT promoter methylation and correlated with clinical data. Results: MGMT methylation status was determined in 25 out of 30 primary glioblastomas by methylation-specific PCR (MSP). MGMT promoter hypermethylation was detected in 12 out of 25 patients (48%). The level of MGMT promoter methylation did not correlate with patients’ gender (p = 0.409), age (p = 0.536), and OS (p = 0.394). Treatment with TMZ significantly prolonged the median survival of a patient (from 5 to 15 months; p < 0.001). Conclusions: Due to a small cohort of primary GBM patients, our study is not sufficient for definitive conclusions regarding the prognostic value of MGMT methylation for the Serbian population. Our preliminary data suggest a lack of association between MGMT promoter methylation and overall survival and a significant correlation of TMZ treatment with overall survival. Further population-based studies are needed to assess the prognostic value of the MGMT promoter methylation status for patients with primary glioblastoma.

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BIOM-59. TERT PROMOTER MUTATION AND MGMT PROMOTER METHYLATION-MEDIATED SENSITIVITY TO TEMOZOLOMIDE IN IDH-WILDTYPE GLIOBLASTOMA: IS THERE A LINK?

Neuro-Oncology ◽

10.1093/neuonc/noaa215.056 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii14-ii14

Author(s):

Dorothee Gramatzki ◽

Jörg Felsberg ◽

Bettina Hentschel ◽

Marietta Wolter ◽

Gabriele Schackert ◽

...

Keyword(s):

Promoter Methylation ◽

Mgmt Promoter Methylation ◽

Tert Promoter Mutation ◽

Promoter Mutation ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Mgmt Promoter ◽

Hotspot Mutations ◽

Promoter Mutations ◽

The Impact

Abstract BACKGROUND Benefit from temozolomide (TMZ) chemotherapy in the treatment of isocitrate dehydrogenase (IDH)-wildtype glioblastoma is essentially limited to patients with O6-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumors. Recent studies suggest that the impact of the MGMT status on chemosensitivity may be modulated by telomerase reverse transcriptase (TERT) promoter hotspot mutations. METHODS MGMT promoter methylation and TERT promoter mutation status were assessed in an exploratory prospective cohort of IDH-wildtype glioblastoma patients of the German Glioma Network (GGN) (n=298) and validated in a retrospective cohort from Düsseldorf, Germany, and Zurich, Switzerland (n=302). RESULTS In the prospective GGN discovery cohort of patients with MGMT promoter-unmethylated tumors, TERT promoter mutation showed inferior outcome (p=0.044). In contrast, TERT promoter mutations were not associated with improved outcome in patients with MGMT promoter-methylated tumors. Different TERT promoter hotspot mutations were not associated with distinct outcomes. The association of TERT promoter mutation in MGMT promoter-unmethylated tumors was not confirmed in the retrospective validation cohort. CONCLUSIONS Analysis of two independent cohorts of glioblastoma patients, including the prospective GGN cohort, did not confirm previous data suggesting that TERT promoter mutations confer an enhanced benefit from TMZ in patients with MGMT promoter-methylated glioblastoma. Thus, diagnostic testing for TERT promoter mutations may not be required for prediction of TMZ sensitivity in IDH-wildtype glioblastoma patients.

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Clinical Significance of Molecular Biomarkers in Glioblastoma

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100010805 ◽

2010 ◽

Vol 37 (5) ◽

pp. 625-630 ◽

Cited By ~ 27

Author(s):

C. Ang ◽

M.-C. Guiot ◽

A. V. Ramanakumar ◽

D. Roberge ◽

P. Kavan

Keyword(s):

Promoter Methylation ◽

Dna Methyltransferase ◽

Mgmt Promoter Methylation ◽

Molecular Biomarkers ◽

Response To Therapy ◽

Wild Type ◽

Egfr Amplification ◽

Mgmt Promoter ◽

Wild Type P53 ◽

The Impact

Aim:To review the impact of molecular biomarkers on response to therapy and survival in patients with primary glioblastoma (GBM).Materials & Methods:Tissue specimens were analyzed for p53 mutations, EGFR amplification, loss of PTEN and p16, and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Demographic and clinical data were gathered from medical records.Results:Clinical and pathological data of 125 patients were collected and analysed. MGMT promoter methylation was associated with improved median overall survival (OS) (61 vs. 42 weeks, p = 0.01) and was an important prognosticator independent of age at diagnosis, extent of resection and post-operative ECOG performance status (HR 2.04, 95% CI 1.11-3.75). Among patients with MGMT promoter methylation, survival was significantly improved with chemoradiotherapy (CRT) over radiotherapy (RT) alone (71 vs. 14 weeks, p < 0.01). Furthermore, amongst those treated with temozolomide (TMZ) based CRT, the presence of EGFR amplification, maintenance of PTEN and wild-type p53 and p16 were each associated with trends towards improved survival.Conclusion:MGMT promoter methylation is a strong, independent prognostic factor for OS in GBM. EGFR amplification, maintenance of PTEN, wild-type p53 and p16 all appear to be associated with improved survival in patients treated with CRT. However, the prognostic value of these biomarkers could not be ascertained and larger prospective studies are warranted.

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