Dataset Information

MGMT methylation may benefit overall survival in patients with moderately vascularized glioblastomas.

ABSTRACT:

Objectives

To assess the combined role of tumor vascularity, estimated from perfusion MRI, and MGMT methylation status on overall survival (OS) in patients with glioblastoma.

Methods

A multicentric international dataset including 96 patients from NCT03439332 clinical study were used to study the prognostic relationships between MGMT and perfusion markers. Relative cerebral blood volume (rCBV) in the most vascularized tumor regions was automatically obtained from preoperative MRIs using ONCOhabitats online analysis service. Cox survival regression models and stratification strategies were conducted to define a subpopulation that is particularly favored by MGMT methylation in terms of OS.

Results

rCBV distributions did not differ significantly (p?>?0.05) in the methylated and the non-methylated subpopulations. In patients with moderately vascularized tumors (rCBV ?10.73), however, there was no significant effect of MGMT methylation (HR?=?1.72, p?=?0.10, AUC?=?0.56).

Conclusions

Our results indicate the existence of complementary prognostic information provided by MGMT methylation and rCBV. Perfusion markers could identify a subpopulation of patients who will benefit the most from MGMT methylation. Not considering this information may lead to bias in the interpretation of clinical studies.

Key points

• MRI perfusion provides complementary prognostic information to MGMT methylation. • MGMT methylation improves prognosis in glioblastoma patients with moderate vascular profile. • Failure to consider these relations may lead to bias in the interpretation of clinical studies.

SUBMITTER: Fuster-Garcia E

PROVIDER: S-EPMC7880975 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

MGMT methylation may benefit overall survival in patients with moderately vascularized glioblastomas.

Fuster-Garcia Elies E Lorente Estellés David D Álvarez-Torres María Del Mar MDM Juan-Albarracín Javier J Chelebian Eduard E Rovira Alex A Acosta Cristina Auger CA Pineda Jose J Oleaga Laura L Mollá-Olmos Enrique E Filice Silvano S Due-Tønnessen Paulina P Meling Torstein R TR Emblem Kyrre E KE García-Gómez Juan M JM

European radiology 20201001 3

<h4>Objectives</h4>To assess the combined role of tumor vascularity, estimated from perfusion MRI, and MGMT methylation status on overall survival (OS) in patients with glioblastoma.<h4>Methods</h4>A multicentric international dataset including 96 patients from NCT03439332 clinical study were used to study the prognostic relationships between MGMT and perfusion markers. Relative cerebral blood volume (rCBV) in the most vascularized tumor regions was automatically obtained from preoperative MRIs ...[more]

PMID: 33001310

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Project description:Glioblastoma (GBM) is the most malignant glioma, with a median overall survival (OS) of 14-16 months. Temozolomide (TMZ) is the first-line chemotherapy drug for glioma, but whether TMZ should be withheld from patients with GBMs that lack O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is still under debate. DNA methylation profiling holds great promise for further stratifying the responses of MGMT promoter unmethylated GBMs to TMZ. In this study, we studied 147 TMZ-treated MGMT promoter unmethylated GBM, whose methylation information was obtained from the HumanMethylation27 (HM-27K) BeadChips (n = 107) and the HumanMethylation450 (HM-450K) BeadChips (n = 40) for training and validation, respectively. In the training set, we performed univariate Cox regression and identified that 3,565 CpGs were significantly associated with the OS of the TMZ-treated MGMT promoter unmethylated GBMs. Functional analysis indicated that the genes corresponding to these CpGs were enriched in the biological processes or pathways of mitochondrial translation, cell cycle, and DNA repair. Based on these CpGs, we developed a 31-CpGs methylation signature utilizing the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm. In both training and validation datasets, the signature identified the TMZ-sensitive GBMs in the MGMT promoter unmethylated GBMs, and only the patients in the low-risk group appear to benefit from the TMZ treatment. Furthermore, these identified TMZ-sensitive MGMT promoter unmethylated GBMs have a similar OS when compared with the MGMT promoter methylated GBMs after TMZ treatment in both two datasets. Multivariate Cox regression demonstrated the independent prognostic value of the signature in TMZ-treated MGMT promoter unmethylated GBMs. Moreover, we also noticed that the hallmark of epithelial-mesenchymal transition, ECM related biological processes and pathways were highly enriched in the MGMT unmethylated GBMs with the high-risk score, indicating that enhanced ECM activities could be involved in the TMZ-resistance of GBM. In conclusion, our findings promote our understanding of the roles of DNA methylation in MGMT umethylated GBMs and offer a very promising TMZ-sensitivity predictive signature for these GBMs that could be tested prospectively.

Dataset Information

MGMT methylation may benefit overall survival in patients with moderately vascularized glioblastomas.

Objectives

Methods

Results

Conclusions

Key points

Publications

MGMT methylation may benefit overall survival in patients with moderately vascularized glioblastomas.

Similar Datasets

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