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Global analysis of the medulloblastoma epigenome identifies disease-subgroup-specific inactivation of COL1A2

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

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Abstract

Candidate gene investigations have indicated a significant role for epigenetic events in the pathogenesis of medulloblastoma, the most common malignant brain tumor of childhood. To assess the medulloblastoma epigenome more comprehensively, we undertook a genomewide investigation to identify genes that display evidence of methylation-dependent regulation. Expression microarray analysis of medulloblastoma cell lines following treatment with a DNA methyltransferase inhibitor revealed deregulation of multiple transcripts (3%-6% of probes per cell line). Eighteen independent genes demonstrated >3-fold reactivation in all cell lines tested. Bisulfite sequence analysis revealed dense CpG island methylation associated with transcriptional silencing for 12 of these genes. Extension of this analysis to primary tumors and the normal cerebellum revealed three major classes of epigenetically regulated genes: (1) normally methylated genes (DAZL, ZNF157, ASN) whose methylation reflects somatic patterns observed in the cerebellum, (2) X-linked genes (MSN, POU3F4, HTR2C) that show disruption of their sex-specific methylation patterns in tumors, and (3) tumor-specific methylated genes (COL1A2, S100A10, S100A6, HTATIP2, CDH1, LXN) that display enhanced methylation levels in tumors compared with the cerebellum. Detailed analysis of COL1A2 supports a key role in medulloblastoma tumorigenesis; dense biallelic methylation associated with transcriptional silencing was observed in 46 of 60 cases (77%). Moreover, COL1A2 status distinguished infant medulloblastomas of the desmoplastic histopathological subtype, indicating that distinct molecular pathogenesis may underlie these tumors and their more favorable prognosis. These data reveal a more diverse and expansive medulloblastoma epi genome than previously understood and provide strong evidence that the methylation status of specific genes may contribute to the biological subclassification of medulloblastoma.


Publication metadata

Author(s): Anderton JA, Lindsey JC, Lusher ME, Gilbertson RJ, Bailey S, Ellison DW, Clifford SC

Publication type: Article

Publication status: Published

Journal: Neuro-oncology

Year: 2008

Volume: 10

Issue: 6

Pages: 981-994

ISSN (print): 1522-8517

ISSN (electronic): 1523-5866

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1215/15228517-2008-048

DOI: 10.1215/15228517-2008-048

PubMed id: 18664619


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Funding

Funder referenceFunder name
American Type Culture Collection
Charlie's Challenge, and the SDBTT Kieron Clark Fund
Katie Trust
Samantha Dickson Brain Tumor Trust
D384MedDr. D. Bigner (Duke University, Durham, NC, USA)
BS-2007-04U. K. Children's Cancer and Leukaemia Group (CCLG)
D425MedDr. D. Bigner (Duke University, Durham, NC, USA)
D556MedDr. D. Bigner (Duke University, Durham, NC, USA)
MEB-MED8AProf. T. Pietsch (University of Bonn Medical Centre, Bonn, Germany)
MHH-MED1Prof. T. Pietsch (University of Bonn Medical Centre, Bonn, Germany)
UW2283Dr. J. Silber (University of Washington, Seattle, WA, USA)

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