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Carcinogenesis Advance Access published online on December 19, 2003
Carcinogenesis, doi:10.1093/carcin/bgh055
© 2003 by Oxford University Press
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© 2003 Oxford University Press

CANCER BIOLOGY

Identification of tumour-specific epigenetic events in medulloblastoma development by hypermethylation profiling

Janet C. Lindsey 1, Meryl E. Lusher 1, Jennifer A. Anderton 1, Simon Bailey 2, Richard J. Gilbertson 3, Andrew D. J. Pearson 1, David W. Ellison 1, and Steven C. Clifford 1*

1 Northern Institute for Cancer Research, The Medical School, University of Newcastle, Newcastle-upon-Tyne, NE2 4HH, UK
2 Sir James Spence Institute of Child Health, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK
3 Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 332 N. Lauderdale Street, Memphis, Tennessee, 38105, USA

* Corresponding author. E-mail: s.c.clifford{at}ncl.ac.uk.

Received 6 August 2003 ; revised 6 November 2003 ; accepted 8 December 2003

Abstract

Medulloblastoma arises in the cerebellum and is the most common malignant brain tumour of childhood, however its molecular basis is not well understood. To assess the role of aberrant epigenetic events in medulloblastoma and identify critical genes in its development, we profiled the promoter methylation status of eleven candidate tumour suppressor genes (TSGs; p14ARF, p15INK4b, p16INK4a, CASP8, HIC1, EDNRB, TIMP3, TP73, TSLC1, RIZ1 and RASSF1A) in medulloblastoma cell lines, primary tumours and the normal cerebellum. Gene-specific TSG methylation was a significant feature of both medulloblastomas and the cerebellum. Extensive hypermethylation of RASSF1A was detected frequently in medulloblastomas but not in the normal cerebellum (41/44 primary tumours vs. 0/5 normal cerebella). In contrast, complete methylation of HIC1 and CASP8 in a subset of primary tumours (17/44 and 14/39) occurred against a consistent background of partial methylation in the normal cerebellum. These data therefore indicate that extensive methylation of RASSF1A, HIC1 and CASP8 are tumour-specific events in medulloblastoma. Moreover, methylation of these genes in medulloblastoma cell lines was associated with their epigenetic transcriptional silencing and methylationdependent re-expression following treatment with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine. The remaining genes studied showed either low frequency methylation (p14ARF, p16INK4a, RIZ1; <7% of cases), no evidence of methylation (p15INK4b, TIMP3, TP73, TSLC1), or comparable patterns of methylation in the normal cerebellum (EDNRB), suggesting that their hypermethylation does not play a major role in medulloblastoma. Our data demonstrate that tumour-specific hypermethylation affects only a subset of genes, and does not support the existence of a concordant methylation phenotype in this disease. We conclude that epigenetic TSG inactivation is a significant feature of medulloblastoma, and identify RASSF1A, HIC1 and CASP8 as potentially critical genes in its pathogenesis. Furthermore, methylation observed in the normal cerebellum emphasises the requirement for appropriate control tissues when assessing the tumour-specificity of TSG hypermethylation.

medulloblastoma, tumour suppressor genes, hypermethylation
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