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The methylome of DDR genes and benefit from RT or TMZ in IDH mutant low grade glioma treated in EORTC 22033

ABSTRACT: Treatment modalities for patients with low grade glioma (LGG) WHO grade II are controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk adjusted treatments are required to preserve cognitive function and quality of life. We aim at identifying mechanisms and associated molecular markers predicting benefit from radiotherapy (RT) or temozolomide (TMZ) on progression free survival in 120 isocitrate dehydrogenase 1 or 2 (IDHmt) mutant LGG treated in the randomized phase III trial EORTC 22033. IDH mutations, the characteristic hallmark of LGG, are associated with a CpG island methylator phenotype (CIMP). Given the genotoxic treatments in this study we determined the DNA methylome of DNA damage response (DDR) genes and assessed the association with progression free survival (PFS). We identified 62 functional CpGs corresponding to 24 of 410 DDR genes in the multidimensional LGG dataset from The Cancer Genome Atlas. Despite the low-powered study, the simulations suggested that seven CpGs, associated with 4 genes could be predictive for PFS in EORTC 22033. Most interestingly, two of the CpGs correspond to MGMT and consisted of the 2 probes used in the MGMT-STP27 classifier. The extent of methylation was predictive for PFS in the TMZ, but not the RT arm. LGG IDHmt and 1p and 19q codeleted that overlap largely with oligodendroglioma displayed a higher extent of MGMT methylation than the IDHmt non-codeleted tumors based on several independent LGG datasets. This is consistent with a better PFS of codeleted patients in the TMZ arm as compared to the non-codeleted patients, while no difference was observed in the RT-arm.

ORGANISM(S): Homo sapiens

PROVIDER: GSE104293 | GEO | 2018/01/31

REPOSITORIES: GEO

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Project description:Purpose: The long-term follow-up results from the EORTC-26951 trial showed that the addition of PCV after radiotherapy increases survival in anaplastic oligodendrogliomas/oligoastrocytomas (AOD/AOA). However, some patients appeared to benefit more from PCV treatment than others. Experimental Design: We performed genome-wide methylation profiling of 115 samples included in the EORTC-26951 trial and extracted the CpG island hypermethylated phenotype (CIMP) and MGMT promoter methylation (MGMT-STP27) status. Results: We first demonstrate that methylation profiling can be performed on archival tissues with a performance that is similar to snap frozen tissue samples. We then performed methylation profiling on EORTC-26951 clinical trial samples. Univariate analysis indicated that CIMP+ or MGMT-STP27 methylated tumors had an improved survival compared to CIMP- and/or MGMT-STP27 unmethylated tumors (median overall survival (OS) 1.05 v. 6.46 years and 1.06 v. 3.8 years, both P<0.0001 for CIMP and MGMT-STP27 status respectively). Multivariable analysis indicates that CIMP and MGMT-STP27 are significant prognostic factors for survival in presence of age, sex performance score and review diagnosis in the model.Multivariate analysis indicates that CIMP and MGMT-STP27 status are prognostic factors for survival independent of age, sex, performance score and review diagnosis. CIMP+ and MGMT-STP27 methylated tumors showed a clear benefit from adjuvant PCV chemotherapy: the median OS of CIMP+ samples in the RT and RT-PCV arms was 3.27 and 9.51 years respectively P=0.0033; for MGMT-STP27 methylated samples it was 1.98 and 8.65 years. There was no such benefit for CIMP- or for MGMT-STP27 unmethylated tumors. MGMT-STP27 status remained significant in an interaction test (P=0.003). Statistical analysis of microarray (SAM) identified 259 novel CpGs associated with treatment response. Conclusions: MGMT-STP27 may be used to guide treatment decisions in this tumor type. Bisulphite converted DNA from the 58 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip The following sample characteristics are provided; OS: overall survival; PFS: progression free survival; CIMP: CpG Island Methylator phenotype; IGS: Intrinsic Glioma subtype; MGMT: O6-methylguanine-DNA-methyltransferase; OR diagn: original diagnosis; Rev diag: review diagnosis; Tum loc: Tumor location; Perf: Performance score; TRT: treatment Performance is based on the ECOG performance status Tum loc: tumor location indicated by 1: Biopsy; 2: Partial Resection; 3: Total Resection. The MGMT promoter methylation status was determined previously (van den Bent et al, J. Clin Oncol 27: 5881-6, 2009) using MS-MLPA and may differ from the MGMT-SPT27 status.

Project description:Purpose: The long-term follow-up results from the EORTC-26951 trial showed that the addition of PCV after radiotherapy increases survival in anaplastic oligodendrogliomas/oligoastrocytomas (AOD/AOA). However, some patients appeared to benefit more from PCV treatment than others. Experimental Design: We performed genome-wide methylation profiling of 115 samples included in the EORTC-26951 trial and extracted the CpG island hypermethylated phenotype (CIMP) and MGMT promoter methylation (MGMT-STP27) status. Results: We first demonstrate that methylation profiling can be performed on archival tissues with a performance that is similar to snap frozen tissue samples. We then performed methylation profiling on EORTC-26951 clinical trial samples. Univariate analysis indicated that CIMP+ or MGMT-STP27 methylated tumors had an improved survival compared to CIMP- and/or MGMT-STP27 unmethylated tumors (median overall survival (OS) 1.05 v. 6.46 years and 1.06 v. 3.8 years, both P<0.0001 for CIMP and MGMT-STP27 status respectively). Multivariable analysis indicates that CIMP and MGMT-STP27 are significant prognostic factors for survival in presence of age, sex performance score and review diagnosis in the model.Multivariate analysis indicates that CIMP and MGMT-STP27 status are prognostic factors for survival independent of age, sex, performance score and review diagnosis. CIMP+ and MGMT-STP27 methylated tumors showed a clear benefit from adjuvant PCV chemotherapy: the median OS of CIMP+ samples in the RT and RT-PCV arms was 3.27 and 9.51 years respectively P=0.0033; for MGMT-STP27 methylated samples it was 1.98 and 8.65 years. There was no such benefit for CIMP- or for MGMT-STP27 unmethylated tumors. MGMT-STP27 status remained significant in an interaction test (P=0.003). Statistical analysis of microarray (SAM) identified 259 novel CpGs associated with treatment response. Conclusions: MGMT-STP27 may be used to guide treatment decisions in this tumor type. Bisulphite converted DNA from the 59 samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip The following sample characteristics are provided; OS: overall survival; PFS: progression free survival; CIMP: CpG Island Methylator phenotype; IGS: Intrinsic Glioma subtype; MGMT: O6-methylguanine-DNA-methyltransferase; OR diagn: original diagnosis; Rev diag: review diagnosis; Tum loc: Tumor location; Perf: Performance score; TRT: treatment Performance is based on the ECOG performance status Tum loc: tumor location indicated by 1: Biopsy; 2: Partial Resection; 3: Total Resection. The MGMT promoter methylation status was determined previously (van den Bent et al, J. Clin Oncol 27: 5881-6, 2009) using MS-MLPA and may differ from the MGMT-SPT27 status.

Project description:Temozolomide (TMZ) is an important first-line treatment for glioblastoma (GBM), but there are limitations to TMZ response in terms of durability and dependence on the promoter methylation status of the DNA repair gene O6-methylguanine DNA methyltransferase (MGMT). MGMT-promoter-hypermethylated (MGMT-M) GBMs are more sensitive to TMZ than MGMT-promoter-hypomethylated (MGMT-UM) GBMs. Moreover, TMZ resistance is inevitable even in TMZ-sensitive MGMT-M GBMs. Hence, epigenetic reprogramming strategies are desperately needed in order to enhance TMZ response in both MGMT-M and MGMT-UM GBMs. In this study, we present novel evidence that the epigenetic reactivation of Tumor Suppressor Candidate 3 (TUSC3) can reprogram sensitivity of GBM stem cells (GSCs) to TMZ irrespective of MGMT promoter methylation status. Interrogation of TCGA patient GBM datasets confirmed TUSC3 promoter regulation of TUSC3 expression and also revealed a strong positive correlation between TUSC3 expression and GBM patient survival. Using a combination of loss-of-function, gain-of-function and rescue studies, we demonstrate that TUSC3 reactivation is associated with enhanced TMZ response in both MGMT-M and MGMT-UM GSCs. Further, we provide novel evidence that the demethylating agent 5-Azacitidine (5-Aza) reactivates TUSC3 expression in MGMT-M GSCs, whereas the combination of 5-Aza and MGMT inhibitor Lomeguatrib is necessary for TUSC3 reactivation in MGMT-UM GSCs. Lastly, we propose a pharmacological epigenetic reactivation strategy involving TUSC3 that leads to significantly prolonged survival in MGMT-M and MGMT-UM orthotopic GSCs models. Collectively, our findings provide a framework and rationale to further explore TUSC3-mediated epigenetic reprogramming strategies that could enhance TMZ sensitivity and outcomes in GBM. Mechanistic and translational evidence gained from such studies could contribute towards optimal design of impactful trials for MGMT-UM GBMs that currently do not have good treatment options.

Project description:This SuperSeries is composed of the SubSeries listed below. BACKGROUND: Gliomas evade current therapies through primary and acquired resistance and the effect of temozolomide is mainly restricted to the subgroup of methylguanin-O6-methyltransferase promoter (MGMT) hypermethylated tumors. Further resistance markers and pathways against chemotherapy and radiotherapy are largely unknown and would help for better stratification. METHODS: The diagnostic cohorts involved clinical data and methylation profiles of the NOA-08 (n = 104, elderly glioblastoma) and the EORTC 26101 (n = 297, glioblastoma) studies and 398 patients with glioblastoma from the Heidelberg center. Twenty-eight glioblastoma CpGs from 17 DNA damage response (DDR) genes that negatively correlate with expression derived from a 450 DDR gene list as well as telomerase reverse transcriptase (TERT) promoter mutations were investigated for outcome and interaction with therapy and classifier assignments. RESULTS: CpG methylation in IDH wildtype tumors had the highest association with the mesenchymal (MES) and receptor tyrosine kinase (RTK) I glioblastoma subgroup. MES tumors have lower tumor purity and differ in copy number variations on chromosomes 7 and 10 from the RTK I and II subtypes. CpG hypomethylation of DDR genes (TP73, CCND3, CSNK1E, EXO1, CUL4A and PRPF19) correlated with worse patient survival in particular in MGMT unmethylated tumors. TERT promoter mutation is most frequent in RTK I and II subtypes and associated with worse survival in primary glioblastoma. Primary glioma cells show methylation pattern that resemble RTK I and II glioma and differ from long term established cell lines. Knock-down of selected resistance genes PRPF19 and TERT increase sensitivity to temozolomide treatment in vitro. CONCLUSION: Methylation of DDR genes and TERT promoter mutations are associated with tumor prognosis, dependent on the methylation cluster and MGMT promoter methylation status in high-grade glioma.

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The methylome of DDR genes and benefit from RT or TMZ in IDH mutant low grade glioma treated in EORTC 22033

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