Carcinogenesis Advance Access originally published online on February 1, 2007
Carcinogenesis 2007 28(6):1264-1268; doi:10.1093/carcin/bgm014
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CpG island promoter hypermethylation of the pro-apoptotic gene caspase-8 is a common hallmark of relapsed glioblastoma multiforme
Department of Neurosurgery, University of Dresden, Fetscherstrasse 74, D-01307-Dresden, Germany,1 Cancer Epigenetics Laboratory, Spanish National Cancer Centre, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernandez Almagro 3, E-28029 Madrid, Spain
2 ENT Department University of Wuerzburg, Josef-Schneider-Street 2, 9-11, D-97080 Wuerzburg, Germany
* To whom correspondence should be addressed. Tel: +49 661 845801; Fax: +49 661 845802; Email: ramon.martinez{at}gmx.net Correspondence may also be addressed to M.Esteller. Tel: +34 91 2246940; Fax: +34 91 2246923; Email: 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 32 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 polymerase chain reaction and selected samples were double checked by bisulfite genomic sequencing. Thirteen genes were analyzed for DNA methylation: the pro-apoptotic CASP8, CASP3, CASP9, DcR1, 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, whereas in 62.5% of patients, differences in the DNA methylation patterns of the 13 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.
Abbreviations: GBM, glioblastoma multiforme; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TSG, tumor suppressor gene; TTP, time to tumor progression;; WHO, World Health Organization
Received September 9, 2006; revised January 16, 2007; accepted January 17, 2007.
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