Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome

Lalezari, Shadi; Chou, Arthur P.; Tran, Anh; Solis, Orestes E.; Khanlou, Négar; Chen, Weidong; Li, Sichen; Carrillo, Jose; Chowdhury, Reshmi; Selfridge, Julia; Sanchez, Daniel R.; Wilson, Ryan W.; Zurayk, Mira; Lalezari, Jonathan; Lou, Jerry J.; Ormiston, Laurel; Ancheta, Karen; Hanna, R.E.B.; Miller, Paul; Piccioni, David; Ellingson, Benjamin M.; Buchanan, Colin; Mischel, Paul S.; Nghiemphu, Phioanh L.; Green, Richard; Wang, He-Jing; Pope, Whitney B.; Liau, Linda M.; Elashoff, Robert M.; Cloughesy, Timothy F.; Yong, William H.; Lai, Albert

doi:10.1093/neuonc/nos308

Cited by 99 publications

(105 citation statements)

References 44 publications

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“…For example, MGMT promoter methylation status was found to be promising prognostic biomarker in patients with glioblastoma multiforme (GBM) treated with radiation and TMZ, as methylated patients demonstrated a median overall survival (OS) of 24.7 months, whereas unmethylated patients demonstrated a median OS of 16.2 months. Progression free survival (PFS) was also higher among methylated than among unmethylated patients (13.3 months vs. 7.8 months) [95]. This is in agreement with results of another study that showed MGMT methylation was correlated with better survival of treated GBM patients with a hazard ratio (HR) of 0.61 [96].…”

Section: Dna Repair Gene Methylation Status As Biomarkersupporting

confidence: 86%

Methylation of DNA repair genes and the efficacy of DNA targeted anticancer treatment

Julsing¹,

Peters²

2014

Oncol Discov

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Cancer is considered both a genetic and epigenetic disease. The best studied epigenetic mechanism in carcinogenesis is DNA methylation, a mechanism which inactivates tumor suppressor genes by methylating their promoters. A subclass of tumor suppressor genes that are often methylated in the process of carcinogenesis are the DNA repair genes. Accumulation of DNA damage is associated with cancer and thus inactivation of DNA repair genes promotes cancer formation. Methylation of DNA repair genes seems to be unique compared to the methylation of other tumor suppressor genes in that it not only promotes tumorigenesis, but at the same time influences the sensitivity of tumors to chemotherapies that are based on agents that damage DNA to kill cancer cells. This literature study summarizes the current knowledge regarding epigenetic inactivation of DNA repair genes and the subsequent progress that has been made coping with the acquired chemotherapy resistances.

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Section: Dna Repair Gene Methylation Status As Biomarkersupporting

confidence: 86%

Methylation of DNA repair genes and the efficacy of DNA targeted anticancer treatment

Julsing¹,

Peters²

2014

Oncol Discov

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“…To date, only one study has specifically used a cohort of patients who received chemoradiotherapy. Lalezari et al (24) reported that their analysis of 418 patients with GBM, including 410 who received chemoradiotherapy with TMZ, indicated that MGMT status, gender, age, KPS score, resection and IDH1 mutations Figure 1. Kaplan-Meier curve of overall survival (A) and progression-free survival (B) in isocitrate dehydrogenase 1/2 (IDH1/2) mutant and IDH1/2 wild-type glioblastoma (GBM) patients.…”

Section: Discussionmentioning

confidence: 99%

Glioblastomas withIDH1/2mutations have a short clinical history and have a favorable clinical outcome

Ohno¹,

Narita²,

Miyakita³

et al. 2015

Jpn. J. Clin. Oncol.

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Objective: Glioblastomas with isocitrate dehydrogenase 1/2 mutations comprise a biologically distinct subgroup of glioblastomas. We studied isocitrate dehydrogenase 1/2 mutant glioblastomas at the clinical, molecular and radiological levels to define their clinical features, including the prognostic value of isocitrate dehydrogenase 1/2 mutations compared with isocitrate dehydrogenase 1/2 wildtype glioblastomas. Methods: We investigated 128 newly diagnosed glioblastoma patients who were treated at our institute between January 2005 and May 2013. Isocitrate dehydrogenase 1/2 mutation status was determined using pyrosequencing. O-6-methylguanine deoxyribonucleic acid methyltransferase promoter methylation and 1p/19q co-deletions were also analyzed using pyrosequencing and multiplex ligation-dependent probe amplification, respectively. Results: Isocitrate dehydrogenase 1/2 mutations were detected in 10 of 128 patients (7.8%). Isocitrate dehydrogenase 1/2 mutations were correlated with a younger age, the presence of an oligodendroglial component and 1p/19q co-deletions and a longer survival time. The interval from initial symptom to initial operation did not differ according to isocitrate dehydrogenase 1/2 mutation status (median interval: 2.3 versus 1.2 months; P = 0.13). Two of three isocitrate dehydrogenase 1/2 mutant glioblastomas harboring 1p/19q co-deletions had an oligodendroglial component and were associated with a prolonged survival time. Multivariate analysis of 90 patients treated with temozolomide-based chemoradiotherapy indicated that age, extent of resection, postoperative Karnofsky performance score and O-6-methylguanine deoxyribonucleic acid methyltransferase promoter methylation were correlated with better survival. Isocitrate dehydrogenase 1/2 mutations showed a trend for improved survival (P = 0.068). Conclusions: Most isocitrate dehydrogenase 1/2 mutant glioblastomas have a short clinical history, and some isocitrate dehydrogenase 1/2 mutant glioblastomas harboring 1p/19q co-deletions behave like oligodendroglial tumors. Isocitrate dehydrogenase 1/2 mutations may have a positive prognostic impact on the Japanese population.

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“…Thus, the MGMT promoter status alone might not be sufficient as marker in a clinical setting. As already described for glioblastoma and NET tumors, we propose that this issue could be overcome by combining promoter methylation with IHC (47,48).…”

Section: /Mgmtmentioning

confidence: 94%

MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide

Erice

Smith

White

et al. 2015

Molecular Cancer Therapeutics

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Melanoma and other solid cancers are frequently resistant to chemotherapies based on DNA alkylating agents such as dacarbazine and temozolomide. As a consequence, clinical responses are generally poor. Such resistance is partly due to the ability of cancer cells to use a variety of DNA repair enzymes to maintain cell viability. Particularly, the expression of MGMT has been linked to temozolomide resistance, but cotargeting MGMT has proven difficult due to dose-limiting toxicities. Here, we show that the MGMT-mediated resistance of cancer cells is profoundly dependent on the DNA repair enzyme PARP. Both in vitro and in vivo, we observe that MGMT-positive cancer cells strongly respond to the combination of temozolomide and PARP inhibitors (PARPi), whereas MGMT-deficient cells do not. In melanoma cells, temozolomide induced an antiproliferative senescent response, which was greatly enhanced by PARPi in MGMTpositive cells. In summary, we provide compelling evidence to suggest that the stratification of patients with cancer upon the MGMT status would enhance the success of combination treatments using temozolomide and PARPi.

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Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome

Abstract: Optimal assessment of MGMT status as a prognostic biomarker for patients with newly diagnosed GBM treated with chemoradiation requires determination of both promoter methylation and IHC protein expression.

Cited by 99 publications

References 44 publications

Methylation of DNA repair genes and the efficacy of DNA targeted anticancer treatment

Methylation of DNA repair genes and the efficacy of DNA targeted anticancer treatment

Glioblastomas withIDH1/2mutations have a short clinical history and have a favorable clinical outcome

MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide

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