Prognostic and predictive value of epigenetic silencing of MGMT in patients with high grade gliomas: a systematic review and meta-analysis

Olson, Robert; Brastianos, Priscilla K.; Palma, David A.

doi:10.1007/s11060-011-0594-5

Cited by 72 publications

(48 citation statements)

References 36 publications

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“…Methylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) promoter is found in about 45% of GBMs occurring in adult patients, causing impaired DNA repair in response to alkylating agents such as temozolomide (150)(151)(152)(153)(154)(155)(156)(157). MGMT promoter methylation is therefore used as a biomarker to predict responsiveness to temozolomide (153,154,157,158). However, both the frequency and the predictive value of MGMT silencing in pediatric HGGs remain controversial, even after collectively more than 1000 children with HGG have been treated with temozolomide in multicenter trials (159)(160)(161)(162).…”

Section: High-grade Gliomasmentioning

confidence: 99%

Molecular mechanisms and therapeutic targets in pediatric brain tumors

et al. 2017

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Brain tumors are among the leading causes of cancer-related deaths in children. Although surgery, aggressive radiation, and chemotherapy have improved outcomes, many patients still die of their disease. Moreover, those who survive often suffer devastating long-term side effects from the therapies. A greater understanding of the molecular underpinnings of these diseases will drive the development of new therapeutic approaches. Advances in genomics and epigenomics have provided unprecedented insight into the molecular diversity of these diseases and, in several cases, have revealed key genes and signaling pathways that drive tumor growth. These not only serve as potential therapeutic targets but also have facilitated the creation of animal models that faithfully recapitulate the human disease for preclinical studies. In this Review, we discuss recent progress in understanding the molecular basis of the three most common malignant pediatric brain tumors-medulloblastoma, ependymoma, and high-grade glioma-and the implications for development of safer and more effective therapies.

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Section: High-grade Gliomasmentioning

confidence: 99%

Molecular mechanisms and therapeutic targets in pediatric brain tumors

et al. 2017

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“…The most complete and most durable responses to temozolomide and the longest overall survival times are seen in the subgroup of tumors with epigenetic silencing of the MGMT enzyme that normally repairs the cytotoxic O 6 -methylguanine (O 6 -MeG) DNA adducts induced by temozolomide (3). However, MGMT methylation status does not correlate with temozolomide sensitivity in all patients, and thus MGMT expression is insufficient to explain temozolomide resistance in all tumors (1,3,4).…”

Section: Introductionmentioning

confidence: 99%

Novel MSH6 Mutations in Treatment-Naïve Glioblastoma and Anaplastic Oligodendroglioma Contribute to Temozolomide Resistance Independently of MGMT Promoter Methylation

Nguyen

Stechishin

Luchman

et al. 2014

Clinical Cancer Research

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Purpose: The current standard of care for glioblastoma (GBM) involves a combination of surgery, radiotherapy, and temozolomide chemotherapy, but this regimen fails to achieve long-term tumor control. Resistance to temozolomide is largely mediated by expression of the DNA repair enzyme MGMT; however, emerging evidence suggests that inactivation of MSH6 and other mismatch repair proteins plays an important role in temozolomide resistance. Here, we investigate endogenous MSH6 mutations in GBM, anaplastic oligodendroglial tumor tissue, and corresponding brain tumor-initiating cell lines (BTIC).Experimental Design: MSH6 sequence and MGMT promoter methylation were determined in human tumor samples and BTICs. Sensitivity to temozolomide was evaluated in vitro using BTICs in the absence and presence of O 6 -benzylguanine to deplete MGMT. The influence of MGMT and MSH6 status on in vivo sensitivity to temozolomide was evaluated using intracranial BTIC xenografts. Results: We identified 11 previously unreported mutations in MSH6 in nine different glioma samples and six paired BTIC lines from adult patients. In addition, MSH6 mutations were documented in three oligodendrogliomas and two treatment-na€ ve gliomas, both previously unreported findings. These mutations were found to influence the sensitivity of BTICs to temozolomide both in vitro and in vivo, independent of MGMT promoter methylation status.Conclusions: These data demonstrate that endogenous MSH6 mutations may be present before alkylator therapy and occur in at least two histologic subtypes of adult glial neoplasms, with this report serving as the first to note these mutations in oligodendroglioma. These findings broaden our understanding of the clinical response to temozolomide in gliomas. Clin Cancer Res; 20(18); 4894-903. Ó2014 AACR.

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“…Thus, it is reasonable to surmise that the prognosis of patients with mutant IDH1 might be favorable. MGMT promoter methylation has been reported as a favorable prognostic factor for survival and a predictive marker for benefit from alkylating agent chemotherapy in patients with GBM (Hegi et al, 2005;Stupp et al, 2009;Olson et al, 2011). It is also found that tumors with methylated MGMT promoter has longer PFS when treated with RT plus chemotherapy compared with patients treated with RT alone (Wick et al, 2013).…”

Section: Discussionmentioning

confidence: 98%

Prognostic Value of MGMT Promoter Methylation and TP53 Mutation in Glioblastomas Depends on IDH1 Mutation

Wang

Wang²,

Ma³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Asian Pac J Cancer Prev, 15 (24), 10893-10898 IntroductionGlioblastoma multiform (GBM), classified as World Health Organization (WHO) grade IV, is the most common malignant brain tumors in adults with an incidence rate of 23 per 100,000 persons (Stancheva et al., 2014). Their clinical course varies substantially, such that some patients succumb to progressive disease within weeks while others survive for a decade or more. Current treatments include surgery, radiation therapy and chemotherapy (Sathornsumetee et al., 2007;Koca et al., 2014;Pashaki et al., 2014). However, the median survival is still not optimistic. In spite of the existing classification, GBM subgroups are not homogeneous in terms of survival (Molenaar et al., 2014). Several prognostic factors have been established, including age, preoperative Karnofsky Performance Status (KPS), extent of resection, and also some molecular markers.Recently, molecular markers were shown to be helpful in predicting prognosis and treatment response. Three gene markers that have attracted most interest in this respect are mutations in the isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) gene (Stancheva et al., 2014), hypermethylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) promoter, and complete deletion of both 1p and 19q. Abstract Several molecular markers have been proposed as predictors of outcome in patients with glioblastomas.We investigated the prognostic significance of O 6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation and TP53 mutation status dependent on isocitrate dehydrogenase 1 (IDH1) mutation in glioblastoma patients. A cohort of 78 patients with histologically confirmed glioblastomas treated with radiation therapy and chemotherapy were reviewed retrospectively. We evaluated the prognostic value of MGMT promoter methylation and TP53 mutation status with regard to progression-free survival (PFS) and overall survival (OS). It was revealed that mutations in IDH1, promoter methylation of MGMT, TP53 mutation, age, Karnofsky performance status (KFS), and extension of resection were independent prognostic factors. In patients with an IDH1 mutation, those with an MGMT methylation were associated with longer PFS (p=0.016) and OS (p=0.013). Nevertheless, the presence of TP53 mutation could stratify the PFS and OS of patients with IDH1 wild type (p=0.003 and 0.029 respectively, log-rank). The MGMT promoter methylation and TP53 mutation were associated with a favorable outcome of patients with and without mutant IDH1, respectively. The results indicate that glioblastomas with MGMT methylation or TP53 mutations have improved survival that may be influenced by IDH1 mutation status.

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Prognostic and predictive value of epigenetic silencing of MGMT in patients with high grade gliomas: a systematic review and meta-analysis

Cited by 72 publications

References 36 publications

Molecular mechanisms and therapeutic targets in pediatric brain tumors

Molecular mechanisms and therapeutic targets in pediatric brain tumors

Novel MSH6 Mutations in Treatment-Naïve Glioblastoma and Anaplastic Oligodendroglioma Contribute to Temozolomide Resistance Independently of MGMT Promoter Methylation

Prognostic Value of MGMT Promoter Methylation and TP53 Mutation in Glioblastomas Depends on IDH1 Mutation

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