MGMT Promoter Methylation and Glioblastoma Prognosis: A Systematic Review and Meta-analysis

Chen, Yang; Hu, Fulan; Zhou, Yiheng; Chen, Wangyang; Shao, Hongbo; Zhang, Ying

doi:10.1016/j.arcmed.2013.04.004

Cited by 52 publications

(32 citation statements)

References 52 publications

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“…The objective of this study was to determine the expression and prognostic value of FZD7 in patients with primary GBM. Furthermore, we sought to identify novel strategies for a more accurate prognosis in these patients by analyzing FZD7 in combination with the previously-described markers MGMT (O-6-methylguanine-DNA methyltransferase) promoter methylation [8] and IDH1 (isocitrate dehydrogenase 1) mutation status [9]. As several studies described the sexually-dimorphic expression of cancer biomarkers including MGMT [10–12], we additionally tested whether our markers exhibited sex-specific differences in relationship to the overall survival of GBM patients.…”

Section: Introductionmentioning

confidence: 99%

Sex-specific clinicopathological significance of novel (Frizzled-7) and established (MGMT, IDH1) biomarkers in glioblastoma

et al. 2016

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BackgroundThe Wnt receptor Frizzled-7 (FZD7) promotes tumor progression and can be currently targeted by monoclonal antibody therapy. Here, we determined the prognostic value of FZD7 for the overall survival of glioblastoma (GBM) patients, both as individual marker and taken in combination with the previously-described markers MGMT and IDH1. Additionally, we tested whether these markers (alone or in combination) exhibited sex-specific differences.ResultsHigh levels of FZD7 (FZD7high) associated with shorter survival in GBM patients; however, FZD7high was a significant predictor of poor survival only in male patients. Mutation of IDH1 significantly associated with longer survival in male but not female patients. Methylated MGMT promoter significantly associated with longer survival only in female patients. Combination of FZD7 with MGMT enhanced the prognostic accuracy and abrogated the sex differences observed upon single marker analysis. Combination of FZD7 with IDH1 was a significant predictor of survival in male GBM patients only.Materials and MethodsThree independent cohorts of patients with primary GBM (n=120, n=108 and n=105, respectively) were included in this study. FZD7 and IDH1 were assessed by immunohistochemistry in tissue microarrays. MGMT promoter methylation was determined by methylation-specific polymerase chain reaction. Survival analysis was performed by Kaplan-Meier estimate, log-rank test and Cox proportional hazard regression.ConclusionsOur study identifies novel individual and combination markers with prognostic and, possibly, therapeutic relevance in GBM. Furthermore, our findings substantiate the importance of sexual dimorphism in this type of cancer.

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Section: Introductionmentioning

confidence: 99%

Sex-specific clinicopathological significance of novel (Frizzled-7) and established (MGMT, IDH1) biomarkers in glioblastoma

et al. 2016

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“…Similarly, epigenetic state can be used to aid in determining prognosis before disease onset, during disease or following treatment [16,48,49,50,51]. As mentioned above, some of these biomarkers have been validated across many studies [34,35,36] and are destined for clinical trials. Outside cancer, notable examples that are yet to be fully validated include predictors of child adiposity [52], progression to overt cardiovascular disease in adults [53] and response to weight loss programs [54,55].…”

Section: The Clinical Use Of Epigenetic Biomarkersmentioning

confidence: 99%

“…It is important to note that, apart from the association of smoking with AHRR methylation, there have been very few EWAS associations replicated in multiple, independent studies. Cancers are the only diseases for which systematic reviews and meta-analyses have demonstrated consistent associations of methylation with disease [33,34,35,36]. …”

Section: Epigenome-wide Association Studiesmentioning

confidence: 99%

“…DOK7 was also differentially methylated in breast cancer tissues and cell lines and, most importantly, was differentially methylated in blood, collected on average 5 years prior to diagnosis. If validated in other cohorts, methylation of DOK7 will join a small number of validated cancer biomarkers that are currently undergoing clinical trials [34,35,36]. …”

Section: Epigenetic Biomarkers From Discordant Mz Twin Ewasmentioning

confidence: 99%

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Epigenetics in Twin Studies

Craig

2013

Med Epigenet

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It is emerging that the environment, particularly in early life, can cause long-lasting epigenetic changes that are accompanied by latent effects on health outcomes. Furthermore, the reversibility of some epigenetic marks in animal models indicates that, once recognised in early life, such epigenetic changes may be reversible, providing potential avenues for disease prognosis, prevention and treatment. Twin studies, which were originally used to calculate gross components of genetic and environmental influence on phenotype, are now being used to associate specific genetic and epigenetic variants with specific human conditions and diseases. Epigenome-wide association studies of phenotypically discordant, genetically ‘identical' monozygotic twins have the power to focus solely on epigenetic association with disease and are providing information about gene-environment interaction and variable penetrance. Going beyond association, such studies can help generate epigenetic biomarkers to predict disease long before clinical onset, which has important implications for disease prevention. Furthermore, when epigenetic information on a genome scale is combined with other ‘omics', twin studies will be a strong force for the improvement of human health.

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“…We know, for example, that hypermethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter region, a mutation present in as few as 30-40% of patients, confers a survival benefit in GBM patients receiving TMZ and radiotherapy, with patients in the Stupp trial demonstrating a 24 month median survival. 1,7 Additionally, a non-telomerase mechanism for maintaining cellular replicative potential known as alternative lengthening of telomeres (ALT) is present in a minority of GBM patients and is known to improve survival. 8 A variety of other markers, such as IDH-1, 1p19q, EGFR, p53, ATRX and TERT to mention a few can also be prognostic and predictive.…”

mentioning

confidence: 99%

Subventricular zone–associated glioblastoma: A call for translational research to guide clinical decision making

2016

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Glioblastoma (GBM) is both the most common and the most devastating primary cancer of the central nervous system, with an expected overall survival in most patients of about 14 months. Despite extensive research, outcomes for GBM have been largely unchanged since the introduction of temozolomide in 2005. We believe that in order to achieve a breakthrough in therapeutic management, we must begin to identify subtypes of GBM, and tailor treatment to best target a particular tumor's vulnerabilities. Our group has recently produced an examination of the clinical outcomes of radiation therapy directed at tumors that contact the subventricular zone (SVZ), the 3-5 mm lateral border of the lateral ventricles that contains the largest collection of neural stem cells in the adult brain. We find that SVZ-associated tumors have worse progression free and overall survival than tumors that do not contact the SVZ, and that they exhibit unique recurrence and migration patterns. However, with minimal basic science research into SVZ-associated GBM, it is currently impossible to determine if the clinicobehavioral uniqueness of this group of tumors represents a true disease subtype from a genetic perspective. We believe that further translational research into SVZ-associated GBM is needed to establish a therapeutic profile.

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MGMT Promoter Methylation and Glioblastoma Prognosis: A Systematic Review and Meta-analysis

Cited by 52 publications

References 52 publications

Sex-specific clinicopathological significance of novel (Frizzled-7) and established (MGMT, IDH1) biomarkers in glioblastoma

Sex-specific clinicopathological significance of novel (Frizzled-7) and established (MGMT, IDH1) biomarkers in glioblastoma

Epigenetics in Twin Studies

Subventricular zone–associated glioblastoma: A call for translational research to guide clinical decision making

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