Epigenetic repression of RASSF1A but not CASP8 in supratentorial PNET (sPNET) and atypical teratoid/rhabdoit tumors (AT/RT) of childhood

Muhlisch J, Schwering A, Grotzer M, Vince GH, Roggendorf W, Hagemann C, Sorensen N, Rickert CH, Osada N, Jurgens H, Fruhwald MC

Research article (journal)

Abstract

Supratentorial primitive neuroectodermal tumors (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of the CNS represent a biological and clinical enigma, despite advances in both molecular techniques and clinical management for these two rare embryonal brain tumors of childhood. Epigenetic changes hold great potential as possible disease mechanisms and may be manipulated therapeutically. We thus studied aberrant methylation of the genes RASSF1A and CASP8 and its consequence on expression in cell lines and primary tumors using a combination of semiquantitative methylation specific PCR (MSP), bisulfite sequencing and RT-PCR. In all, 17 samples of autopsy-derived normal appearing brain served as controls. Opposed to control tissues 19/24 sPNET and 4/6 AT/RT demonstrated aberrant methylation for the RASSF1A promoter region. Treatment of cell lines using 5-Aza-2'-deoxycytidine (5AZA) alone or in combination with trichostatin A (TSA) succeeded in re-establishing expression of RASSF1A in cell lines derived from a renal rhabdoid, an AT/RT and a medulloblastoma. A 5'-CpG-rich region of CASP8 was methylated in normal tissues and in tumors. However, CASP8 showed inconsistent expression patterns in normal and tumor tissues. Our results indicate that aberrant methylation of the RASSF1A promoter region maybe of importance in the origin and progression of sPNET and AT/RT while the analysed 5'-CpG rich region of the CASP8 gene does not seem to play an important role in these tumors. Further studies of epigenetic changes in these rare tumors are warranted as their biology remains obscure and treatment efforts have been rather unsuccessfull.

Details about the publication

JournalOncogene
Volume25
Issue7
Page range1111-1117
StatusPublished
Release year2006 (28/02/2006)
Language in which the publication is writtenEnglish
DOI10.1038/sj.onc.1209137
Keywordsbrain tumors epigenetics methylation childhood sPNET AT; RT primitive neuroectodermal tumors comparative genomic hybridization central-nervous-system aberrant promoter methylation medulloblastoma development molecular analysis pediatric tumors suppressor gene rhabdoid tumors cell-lines

Authors from the University of Münster

Frühwald, Michael Christoph
University Children's Hospital - Department of Paediatric Haematology and Oncology (UKM PHO)
Jürgens, Franz Herbert
University Children's Hospital - Department of Paediatric Haematology and Oncology (UKM PHO)
Mühlisch, Jörg
University Children's Hospital - Department of Paediatric Haematology and Oncology (UKM PHO)