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

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• 作者：Amandine Etcheverry (1) (2) (3)
  Marc Aubry (3)
  Marie de Tayrac (4)
  Elodie Vauleon (1) (5)
  Rachel Boniface (1)
  Frederique Guenot (2) (3)
  Stephan Saikali (6)
  Abderrahmane Hamlat (7)
  Laurent Riffaud (7)
  Philippe Menei (8)
  Veronique Quillien (1) (5)
  Jean Mosser (1) (2) (3)
  
• 刊名：BMC Genomics
• 出版年：2010
• 出版时间：December 2010
• 年：2010
• 卷：11
• 期：1
• 全文大小：5924KB
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• 作者单位：Amandine Etcheverry (1) (2) (3)
  Marc Aubry (3)
  Marie de Tayrac (4)
  Elodie Vauleon (1) (5)
  Rachel Boniface (1)
  Frederique Guenot (2) (3)
  Stephan Saikali (6)
  Abderrahmane Hamlat (7)
  Laurent Riffaud (7)
  Philippe Menei (8)
  Veronique Quillien (1) (5)
  Jean Mosser (1) (2) (3)
  
  1. CNRS UMR6061 Institut de G茅n茅tique et D茅veloppement, Universit茅 de Rennes 1, UEB, IFR140, Rennes, France
  2. Service de G茅n茅tique Mol茅culaire et G茅nomique, CHU Rennes, France
  3. Plateforme G茅nomique Sant茅 Biogenouest庐 Rennes, France
  4. INSERM U946, Fondation Jean Dausset, CEPH, Paris, France
  5. D茅partement de Biologie M茅dicale, Centre Eug猫ne Marquis, Rennes, France
  6. Service d'Anatomie et Cytologie Pathologique, CHU Rennes, France
  7. Service de Neurochirurgie, CHU Rennes, France
  8. Service de Neurochirurgie, CHU Angers, France
  

文摘

Background 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. Results We performed a whole-genome integrative analysis of methylation and gene expression profiles in 40 newly diagnosed glioblastoma patients. We also screened for associations between the level of methylation of CpG sites and overall survival in a cohort of 50 patients uniformly treated by surgery, 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 of which was differentially expressed in a concordant way. Thirteen of the genes with concordant CpG sites displayed an inverse correlation between promoter methylation and expression level in glioblastomas: B3GNT5, FABP7, ZNF217, BST2, OAS1, SLC13A5, GSTM5, ME1, UBXD3, TSPYL5, FAAH, C7orf13, and C3orf14. Survival analysis identified six CpG sites associated with overall survival. SOX10 promoter methylation status (two CpG sites) stratified patients similarly to MGMT status, but with a higher Area Under the Curve (0.78 vs. 0.71, p- value < 5e-04). The methylation status of the FNDC3B, TBX3, DGKI, and FSD1 promoters identified patients with MGMT -methylated tumors that did not respond to STUPP treatment (p- value < 1e-04). Conclusions This study provides the first genome-wide integrative analysis of DNA methylation and gene expression profiles obtained from the same GBM cohort. We also present a methylome-based survival analysis for one of the largest uniformly treated GBM cohort ever studied, for more than 27,000 CpG sites. We have identified genes whose expression may be tightly regulated by epigenetic mechanisms and markers that may guide treatment decisions.