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The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space

ABSTRACT: Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of DNA methylation in matched primary and recurring glioblastoma tumors, using data from a highly annotated clinical cohort that was selected through a national patient registry. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected FFPE samples, and we validate bisulfite sequencing as a multipurpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional characteristics of the profiled tumor samples. On the basis of these data, we identified subtle differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study establishes an open resource for dissecting DNA methylation heterogeneity in a genetically diverse and heterogeneous cancer, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology for a national cohort, thereby leveraging existing samples and data collected as part of routine clinical practice.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100351 | GEO | 2018/06/20

REPOSITORIES: GEO

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The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space

Project description:Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of DNA methylation in matched primary and recurring glioblastoma tumors, using data from a highly annotated clinical cohort that was selected through a national patient registry. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected FFPE samples, and we validate bisulfite sequencing as a multipurpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional characteristics of the profiled tumor samples. On the basis of these data, we identified subtle differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study establishes an open resource for dissecting DNA methylation heterogeneity in a genetically diverse and heterogeneous cancer, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology for a national cohort, thereby leveraging existing samples and data collected as part of routine clinical practice.

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Intra-Tumor DNA Methylation Heterogeneity in Glioblastoma Implications for DNA Methylation-based Classification

Project description:Intra-Tumor DNA Methylation Heterogeneity in Glioblastoma Implications for DNA Methylation-based Classification

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DNA Methylation Profiling of Glioblastoma: Impact on Gene Expression and Clinical Outcome (Illumina)

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Project description:Genome-scale measurements of DNA methylation levels are necessary to decipher the epigenetic events involved in glioblastoma aggressive phenotype, and to guide new therapeutic strategies. In that purpose, we performed a whole genome integrative analysis of the methylation and expression profiles for 40 newly diagnosed glioblastoma patients. We have also screened for associations between CpG sites methylation levels and overall survival in a cohort of 50 patients uniformly treated with radiotherapy and chemotherapy with concomitant and adjuvant temozolomide (STUPP protocol). The methylation analysis identified 616 CpG sites differentially methylated between glioblastoma and control brain, a quarter being differentially expressed in a concordant way. Among these concordant CpG sites, 13 genes displayed, within our glioblastoma cohort, an inverse correlation between promoter methylation and expression levels: B3GNT5, FABP7, ZNF217, BST2, OAS1, SLC13A5, GSTM5, ME1, UBXD3, TSPYL5, FAAH, C7orf13, and C3orf14. The expression of these genes may be tightly regulated by epigenetic mechanisms. The survival analysis identified six CpG sites associated with overall survival. The SOX10 promoter methylation status (two CpG sites) stratifies the patients in a way similar to MGMT with improved performance based on Area Under the Curve criteria (0.78 vs. 0.71, p-value < 5.10-4). The methylation status of FNDC3B, TBX3, DGKI, and FSD1 promoters identify patients with MGMT methylated tumors non-responding to STUPP treatment (p-value < 1.10-4). These markers have a potential impact on therapeutic decision. 40 glioblastoma samples and 6 control brain samples were analysed. 2 distinct series of hybridizations were carried out, each containing GBMs and control brains.

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