Carcinogenesis Advance Access published online on February 1, 2007
Carcinogenesis, doi:10.1093/carcin/bgm014
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CpG island promoter hypermethylation of the pro-apoptotic gene caspase-8 is a common hallmark of relapsed glioblastoma multiforme
1 Department of Neurosurgery of the University of Dresden, Fetscherstr. 74, D-01307-Dresden, Germany
2 Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, E-28029 Madrid, Spain
3 ENT Department University of Wuerzburg, Josef-Schneider-Str. 2, 9-11, D-97080 Wuerzburg, Germany
Corresponding author and request for reprints: Ramon Martinez MD, Department of Neurosurgery, Klinikum Fulda, Academic Hospital Philipps-University Marburg, Pacelliallee 4, D-36043 Fulda, Germany. Phone: 49-661-845801, Fax: 49-661-845802. E-mail: ramon.martinez{at}gmx.net or Manel Esteller MD, Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain. Fax: 34-91-2246923. E-mail: mesteller{at}cnio.es
Glioblastoma multiforme (GBM) is an incurable malignancy with inherent tendency to recur. In this study we have comparatively analyzed the epigenetic profile of thirty-two paired tumor samples of relapsed GBM and their corresponding primary neoplasms with special attention to genes involved in the mitochondria-independent apoptotic pathway. The CpG island promoter hypermethylation status was assessed by methylation-specific PCR and selected samples were double-checked by bisulfite genomic sequencing. Thirteen genes were analyzed for DNA methylation: the pro-apoptotic CASP8, CASP3, CASP9, DcR 1, DR4, DR5, and TMS1; the cell adherence CDH1 and CDH13; the candidate tumor suppressor RASSF1A and BLU; the cell-cycle regulator CHFR; and the DNA repair MGMT. The CpG island promoter hypermethylation profile of relapsed GBM in comparison with their corresponding primary tumors was identical in 37.5% of the cases, while in 62.5% of patients differences in the DNA methylation patterns of the thirteen genes were observed. The most prominent distinction was the presence of previously undetected CASP8 hypermethylation in the GBM relapses (P= 0.031). This finding was also linked to the observation that an unmethylated CASP8 CpG island together with methylated BLU promoter in the primary GBM was associated with prolonged time to tumor progression (P= 0.0035). Our data strongly suggest that hypermethylation of the pro-apoptotic CASP8 is a differential feature of GBM relapses. These remarkable findings may foster the development of therapeutic approaches using DNA demethylating drugs and activators of the extrinsic apoptotic pathway to improve the dismal prognosis of GBM.
Key Words: CpG island • hypermethylation • glioblastoma • caspase-8 • BLU
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Elias, M. D. Siegelin, A. Steinmuller, A. von Deimling, U. Lass, B. Korn, and W. Mueller Epigenetic Silencing of Death Receptor 4 Mediates Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Resistance in Gliomas Clin. Cancer Res., September 1, 2009; 15(17): 5457 - 5465. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Ghavami, M Hashemi, S R Ande, B Yeganeh, W Xiao, M Eshraghi, C J Bus, K Kadkhoda, E Wiechec, A J Halayko, et al. Apoptosis and cancer: mutations within caspase genes J. Med. Genet., August 1, 2009; 46(8): 497 - 510. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Frosina DNA Repair and Resistance of Gliomas to Chemotherapy and Radiotherapy Mol. Cancer Res., July 1, 2009; 7(7): 989 - 999. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Bethke, K. Sullivan, E. Webb, A. Murray, M. Schoemaker, A. Auvinen, A. Kiuru, T. Salminen, C. Johansen, H. C. Christensen, et al. The Common D302H Variant of CASP8 Is Associated with Risk of Glioma Cancer Epidemiol. Biomarkers Prev., April 1, 2008; 17(4): 987 - 989. [Abstract] [Full Text] [PDF]
|
|