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

Lookup NU author(s): Dr Janet Lindsey, Dr Meryl Lusher, Jennifer Anderton, Professor Simon Bailey, Dr Richard Gilbertson, Professor Andrew Pearson, Professor David Ellison, Professor Steven Clifford

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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 11 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 versus 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 methylation-dependent re-expression following treatment with the DNA methyl-transferase 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. © Oxford University Press 2004; all rights reserved.


Publication metadata

Author(s): Lindsey JC, Lusher ME, Anderton J, Bailey S, Gilbertson R, Pearson ADJ, Ellison DW, Clifford SC

Publication type: Article

Publication status: Published

Journal: Carcinogenesis

Year: 2004

Volume: 25

Issue: 5

Pages: 661-668

Print publication date: 01/05/2004

ISSN (print): 0143-3334

ISSN (electronic): 1460-2180

URL: http://dx.doi.org/10.1093/carcin/bgh055

DOI: 10.1093/carcin/bgh055

PubMed id: 14688019


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