Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

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

ABSTRACT: 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. 55 glioblastoma samples and 3 control brain samples were analysed.

ORGANISM(S): Homo sapiens

SUBMITTER: Amandine Etcheverry

PROVIDER: E-GEOD-22867 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

DNA methylation in glioblastoma: impact on gene expression and clinical outcome.

Etcheverry Amandine A Aubry Marc M de Tayrac Marie M Vauleon Elodie E Boniface Rachel R Guenot Frederique F Saikali Stephan S Hamlat Abderrahmane A Riffaud Laurent L Menei Philippe P Quillien Veronique V Mosser Jean J

BMC genomics 20101214

<h4>Background</h4>Changes in promoter DNA methylation pattern of genes involved in key biological pathways have been reported in glioblastoma. Genome-wide assessments of DNA methylation levels are now required to decipher the epigenetic events involved in the aggressive phenotype of glioblastoma, and to guide new treatment strategies.<h4>Results</h4>We performed a whole-genome integrative analysis of methylation and gene expression profiles in 40 newly diagnosed glioblastoma patients. We also s ...[more]

PMID: 21156036

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Project description:Pathologic differentiation of tissue of origin in tumors found in the lung can be challenging, with differentiation of mesothelioma and lung adenocarcinoma emblematic of this problem. Indeed, proper classification is essential for determination of treatment regimen for these diseases, making accurate and early diagnosis critical. Here we investigate the potential of epigenetic profiles of lung adenocarcinoma, mesothelioma, and non-malignant pulmonary tissues (n=285) as differentiation markers in an analysis of DNA methylation at 1413 autosomal CpG loci associated with 773 cancer-related genes. Using an unsupervised recursively-partitioned mixture modeling technique for all samples, the derived methylation profile classes were significantly associated with sample type (P < 0.0001). In a similar analysis restricted to tumors, methylation profile classes significantly predicted tumor type (P < 0.0001). Random forests classification of CpG methylation of tumors - which splits the data into training and test sets - accurately differentiated MPM from lung adenocarcinoma over 99% of the time (P < 0.0001). In a locus-by-locus comparison of CpG methylation between tumor types, 1266 CpG loci had significantly different methylation between tumors following correction for multiple comparisons (Q < 0.05); 61% had higher methylation in adenocarcinoma. Using the CpG loci with significant differential methylation in a pathways analysis revealed significant enrichment of methylated gene-loci in Cell Cycle Regulation, DNA Damage Response, PTEN Signaling, and Apoptosis Signaling pathways in lung adenocarcinoma when compared to mesothelioma. Methylation-profile-based differentiation of lung adenocarcinoma and mesothelioma is highly accurate, informs on the distinct etiologies of these diseases, and holds promise for clinical application. Mesotheliomas (n=158) and grossly non-tumorigenic parietal pleura (n=18) were obtained following surgical resection at Brigham and Womenâ??s Hospital through the International Mesothelioma Program from a pilot study conducted in 2002 (n=70) and an incident case series beginning in 2005 (n=88) with a participation rate of 85%. We used biopsy specimens from patients treated for NSCLC at the Massachusetts General Hospital from 1992 â?? 1996 (18) including lung adenocarcinomas (n=57) and non-malignant pulmonary tissues (n=48) (of which 22 (39%) were taken from the adenocarcinoma patients) (18). Additional normal lung tissues were obtained from the National Disease Research Interchange from donors free of lung malignancy (n=4).

Dataset Information

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

Publications

DNA methylation in glioblastoma: impact on gene expression and clinical outcome.

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