Frequent hypermethylation of the DNA repair gene MGMT in long-term survivors of glioblastoma multiforme

Martínez, Ramón; Schackert, Gabriele; Yaya-Tur, Ricardo; Rojas-Marcos, Íñigo; Herman, James G.; Esteller, Manel

doi:10.1007/s11060-006-9292-0

Cited by 95 publications

(65 citation statements)

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“…The dependency of MGMT on the expression levels of mGlu3 receptors might help to explain the controversial data on the correlation between MGMT promoter methylation and patients' survival. [34][35][36][37][38][39][40] Our data may pave the way to a new strategy in the pharmacological treatment of malignant gliomas because mGlu3 receptor antagonists could be added to temozolomide or other DNA-alkylating agents for the optimization of adjuvant chemotherapy. The evidence that a combined treatment with temozolomide and LY341495 was still efficacious in restraining tumor growth when initiated 45 days after cell implantation in mice is particularly promising for translation into medical practice because of the long interval between onset and treatment of malignant gliomas.…”

Section: Discussionmentioning

confidence: 87%

Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

et al. 2012

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Drug treatment of malignant gliomas is limited by the intrinsic resistance of glioma stem cells (GSCs) to chemotherapy. GSCs isolated from human glioblastoma multiforme (GBM) expressed metabotropic glutamate receptors (mGlu3 receptors). The DNAalkylating agent, temozolomide, killed GSCs only if mGlu3 receptors were knocked down or pharmacologically inhibited. In contrast, mGlu3 receptor blockade did not affect the action of paclitaxel, etoposide, cis-platinum, and irinotecan. mGlu3 receptor blockade enabled temozolomide toxicity by inhibiting a phosphatidylinositol-3-kinase/nuclear factor-jB pathway that supports the expression of O 6 -methylguanine-DNA methyltransferase (MGMT), an enzyme that confers resistance against DNAalkylating agents. In mice implanted with GSCs into the brain, temozolomide combined with mGlu3 receptor blockade substantially reduced tumor growth. Finally, 87 patients with GBM undergoing surgery followed by adjuvant chemotherapy with temozolomide survived for longer time if tumor cells expressed low levels of mGlu3 receptors. In addition, the methylation state of the MGMT gene promoter in tumor extracts influenced survival only in those patients with low expression of mGlu3 receptors in the tumor. These data encourage the use of mGlu3 receptor antagonists as add-on drugs in the treatment of GBM, and suggest that the transcript of mGlu3 receptors should be measured in tumor specimens for a correct prediction of patients' survival in response to temozolomide treatment.

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Section: Discussionmentioning

confidence: 87%

Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

et al. 2012

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“…PTEN. [7][8][9] Recent studies demonstrated that mutations in IDH1 10 and alterations in multiple networking genes (POLD2, CYCS, MYC, AKR1C3, YME1L1, ANXA7, and PDCD4) 11 were associated with GBM survival. Polymorphisms in TERT, 12 IL4R, 13 EGF, 14,15 and CX3CR1 16 genes and GBM survival have also been described.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 Genes Involved in the Double-Strand Break Repair Pathway Predict Glioblastoma Survival

Liu

Shete

Etzel

et al. 2010

JCO

101

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A B S T R A C T PurposeGlioblastoma (GBM) is the most common and aggressive type of glioma and has the poorest survival. However, a small percentage of patients with GBM survive well beyond the established median. Therefore, identifying the genetic variants that influence this small number of unusually long-term survivors may provide important insight into tumor biology and treatment. Patients and MethodsAmong 590 patients with primary GBM, we evaluated associations of survival with the 100 top-ranking glioma susceptibility single nucleotide polymorphisms from our previous genomewide association study using Cox regression models. We also compared differences in genetic variation between short-term survivors (STS; Յ 12 months) and long-term survivors (LTS; Ն 36 months), and explored classification and regression tree analysis for survival data. We tested results using two independent series totaling 543 GBMs. ResultsWe identified LIG4 rs7325927 and BTBD2 rs11670188 as predictors of STS in GBM and CCDC26 rs10464870 and rs891835, HMGA2 rs1563834, and RTEL1 rs2297440 as predictors of LTS. Further survival tree analysis revealed that patients Ն 50 years old with LIG4 rs7325927 (V) had the worst survival (median survival time, 1.2 years) and exhibited the highest risk of death (hazard ratio, 17.53; 95% CI, 4.27 to 71.97) compared with younger patients with combined RTEL1 rs2297440 (V) and HMGA2 rs1563834 (V) genotypes (median survival time, 7.8 years). ConclusionPolymorphisms in the LIG4, BTBD2, HMGA2, and RTEL1 genes, which are involved in the double-strand break repair pathway, are associated with GBM survival.

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“…Hence, with decreased expression of MGMT, because of methylation of its promoter, the therapeutic efficacy of temozolomide is enhanced. 89 That patient survival times differ according to MGMT status underscores the significance of understanding the diversity of tumor biology. Such an understanding can be of immense importance with regard to CSCs because activity of MGMT has been shown to be 32-to 56-fold higher in CD133-positive than in CD133-negative cells, leading to increased resistance to temozolomide.…”

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confidence: 99%

Targeting glioblastoma cancer stem cells: the next great hope?

Khan

Ehtesham

2014

FOC

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Glioblastoma multiforme (GBM) is the most common primary brain tumor and is notorious for its poor prognosis. The highly invasive nature of GBM and its inherent resistance to therapy lead to very high rates of recurrence. Recently, a small cohort of tumor cells, called cancer stem cells (CSCs), has been recognized as a subset of tumor cells with self-renewal ability and multilineage capacity. These properties, along with the remarkable tumorigenicity of CSCs, are thought to account for the high rates of tumor recurrence after treatment. Recent research has been geared toward understanding the unique biological characteristics of CSCs to enable development of targeted therapy. Strategies include inhibition of CSC-specific pathways and receptors; agents that increase sensitivity of CSCs to chemotherapy and radiotherapy; CSC differentiation agents; and CSC-specific immunotherapy, virotherapy, and gene therapy. These approaches could inform the development of newer therapeutics for GBM. Key WordS • glioblastoma multiforme • cancer stem cells • treatment • tumor-initiating cells • glioma stem cellsAbbreviations used in this paper: Akt = protein kinase B; BCNU = 1,3-bis(2-chloroethyl)-1-nitrosourea; CSC = cancer stem cell; EGFR = epidermal growth factor receptor; GBM = glioblastoma multiforme; MGMT = methylguanine-DNA methyltransferase; STAT3 = signal transducer and activator of transcription 3; TGFb = transforming growth factor-b.

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Frequent hypermethylation of the DNA repair gene MGMT in long-term survivors of glioblastoma multiforme

Cited by 95 publications

References 3 publications

Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 Genes Involved in the Double-Strand Break Repair Pathway Predict Glioblastoma Survival

Targeting glioblastoma cancer stem cells: the next great hope?

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