Association of<i>MGMT</i>Promoter Methylation Status With Survival Outcomes in Patients With High-Risk Glioma Treated With Radiotherapy and Temozolomide

Bell, Erica H.; Zhang, Peixin; Fisher, Barbara; Macdonald, David R.; McElroy, Joseph P.; Lesser, Glenn J.; Fleming, Jessica L.; Chakraborty, Arup; Liu, Ziyan; Becker, Aline Paixão; Fabian, Denise; Aldape, Kenneth; Ashby, Lynn S.; Werner‐Wasik, Maria; Walker, Eleanor M.; Bahary, Jean Paul; Kwok, Young; Yu, Hsiang‐Hsuan Michael; Laack, Nadia N.; Schultz, Christopher J.; Gray, Heidi J.; Robins, H. Ian; Mehta, Minesh P.; Chakravarti, Arnab

doi:10.1001/jamaoncol.2018.1977

Cited by 135 publications

(119 citation statements)

References 17 publications

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“…Most interestingly, we found that SRD5A2 methylation in promoter regions, specifically at CpG# -39 to CpG# -2, is significantly associated with better survival for CRPC patients treated with ADT. Being consistent with the study for high-risk gliomas which showed that MGMT promoter methylation predicts better survival outcomes [30], our finding not only provides evidence that alteration of the epigenome is an important step in cancer progression, but also opens new windows of opportunities in personalized medicine for CRPC patients.…”

Section: Srd5a2 Promoter Methylation Was Negatively Associated With Ssupporting

confidence: 91%

Methylation of SRD5A2 promoter predicts a better outcome for castration-resistant prostate cancer patients undergoing androgen deprivation therapy

et al. 2020

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PurposeTo determine whether SRD5A2 promoter methylation is associated with cancer progression during androgen deprivation therapy (ADT) in CRPC.analysis showed that SRD5A2 methylation was associated with OS independently (whole promoter region: P = 0.035; specific region: P = 0.02). ConclusionOur study demonstrate that SRD5A2 methylation in promoter regions, specifically at CpG# -39 to -2, is significantly associated with better survival for CRPC patients treated with ADT. Recognition of epigenetic modifications of SRD5A2 may affect the choices and sequence of available therapies for management of CRPC. PLOS ONESRD5A2 methylation predicts a better outcome for CRPC PLOS ONE | https://doi.org/10.

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Section: Srd5a2 Promoter Methylation Was Negatively Associated With Ssupporting

confidence: 91%

Methylation of SRD5A2 promoter predicts a better outcome for castration-resistant prostate cancer patients undergoing androgen deprivation therapy

et al. 2020

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“…According to Reuss et al ., the characteristic pattern of IDH mutant astrocytic lineage tumors (DA, AA, GBM) is the presence of coexisting loss of nuclear ATRX, and sometimes of strong diffuse nuclear p53 immunostaining. ATRX loss is caused by corresponding gene mutations, while s trong p53 immunostaining in > 10% neoplastic cells is highly correlated with TP53 mutation in diffuse gliomas . In this study, 41% of IDH mutant astrocytomas had no ATRX mutation/protein loss, which is in line with ATRX retention previously found in IDH mutant diffuse gliomas from patients at ≥ 55 years in other studies .…”

Section: Discussionsupporting

confidence: 90%

Diffuse gliomas in patients aged 55 years or over: A suggestion for IDH mutation testing

et al. 2019

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Diffuse gliomas are defined on the isocitrate dehydrogenase (IDH) gene (IDH) mutational mutational status. The most frequent IDH mutation is IDH1 R132H, which is detectable by immunohistochemistry; other IDH mutations are rare (10%). IDH mutant gliomas have better prognosis. Further, IDH wild-type low-grade (II/III) gliomas have clinical behaviors similar to those of glioblastoma (GBM) and it was suggested that they are submitted to similar post-surgical treatment. The incidence of IDH mutant gliomas (2%) and that of GBMs with non-canonical IDH mutations (< 1%) are very low in patients ≥ 55 years. For this reason, it was suggested that immunohistochemistry against IDH1 R132H is sufficient to classify GBM as IDH wild-type in this age group. However, no indication was provided for IDH mutational testing in low-grade diffuse gliomas. To address this issue, 273 diffuse gliomas were tested for IDH1 R132H immunohistochemistry. 2/4 diffuse astrocytomas (DAs), 4/9 anaplastic astrocytomas (AAs), 2/256 GBMs, and 4/4 oligodendrogliomas had positive staining. No other IDH mutations were found in immuno-negative low-grade cases by DNA sequencing. To validate our findings, we considered 311 diffuse gliomas in patients ≥ 55 years in The Cancer Genome Atlas database. Fifty-five out of 311 gliomas had IDH R132H mutations (9/16 DAs; 8/48 AAs; 3/211 GBMs; 35/36 oligodendrogliomas), one DA, and one oligodendroglioma had other IDH mutations. IDH mutant gliomas had significantly higher frequency of O-6-methylguanine-DNA methyltransferase promoter methylation (P = 0.0008) and longer overall survival (P < 0.0001).In conclusion, low-grade gliomas are a minor part of gliomas (117/584) in patients ≥ 55 years, albeit they represent most IDH mutant gliomas in this age group (64/69 cases). IDH non-canonical mutations can be found in immunonegative low-grade gliomas (2/54). In view of its significance for prognosis and therapeutic management, our results suggest that IDH mutational status is assessed in all diffuse gliomas in patients ≥ 55 years by immunohistochemistry, followed by IDH sequencing in low-grade immunonegative cases.

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“…Methylation of the MGMT promoter leads to low expression of MGMT and inactivation of the repair protein, rendering tumor cells more sensitive to effects of alkylating agents [39]. Consequently, MGMT methylation is considered a favorable prognosis marker associated with longer survival outcomes [40].…”

Section: Discussionmentioning

confidence: 99%

The interaction between TERT promoter mutation and MGMT promoter methylation on overall survival of glioma patients: a meta-analysis

Vuong

Nguyen

Ngo

et al. 2020

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Background There are controversial results concerning the prognostic implication of TERT promoter mutation in glioma patients concerning MGMT status. In this meta-analysis, we investigated whether there are any interactions of these two genetic markers on the overall survival (OS) of glioma patients. Methods Electronic databases including PubMed and Web of Science were searched for relevant studies. Hazard ratio (HR) and its 95% confidence interval (CI) for OS adjusted for selected covariates were calculated from the individual patient data (IPD), Kaplan-Meier curve (KMC), or directly obtained from the included studies. Results A total of nine studies comprising 2819 glioma patients were included for meta-analysis. Our results showed that TERT promoter mutation was associated with a superior outcome in MGMT-methylated gliomas (HR = 0.73; 95% CI = 0.55-0.98; p-value = 0.04), whereas this mutation was associated with poorer survival in gliomas without MGMT methylation (HR = 1.86; 95% CI = 1.54-2.26; p-value < 0.001). TERT-mutated glioblastoma (GBM) patients with MGMT methylation benefited from temozolomide (TMZ) treatment (HR = 0.33; 95% CI = 0.23-0.47; p-value < 0.001). MGMT methylation was not related with any improvement in OS in TERT-wild type GBMs (HR = 0.80; 95% CI = 0.56-1.15; p-value = 0.23).ConclusionsThe prognostic value of TERT promoter mutation may be modulated by MGMT methylation status. Not all MGMT-methylated GBM patients may benefit from TMZ; it is possible that only TERT-mutated GBM with MGMT methylation, in particular, may respond.

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Association ofMGMTPromoter Methylation Status With Survival Outcomes in Patients With High-Risk Glioma Treated With Radiotherapy and Temozolomide

Abstract: ClinicalTrials.gov Identifier: NCT00114140.

Cited by 135 publications

References 17 publications

Methylation of SRD5A2 promoter predicts a better outcome for castration-resistant prostate cancer patients undergoing androgen deprivation therapy

Methylation of SRD5A2 promoter predicts a better outcome for castration-resistant prostate cancer patients undergoing androgen deprivation therapy

Diffuse gliomas in patients aged 55 years or over: A suggestion for IDH mutation testing

The interaction between TERT promoter mutation and MGMT promoter methylation on overall survival of glioma patients: a meta-analysis

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