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

¹ Northern Institute for Cancer Research, The Medical School, Newcastle University, Newcastle-upon-Tyne, NE2 4HH, U.K.
² Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, U.S.A.
³ Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 38105, U.S.A.

^* To whom correspondence should be addressed. E-mail: s.c.clifford{at}ncl.ac.uk.

	Abstract

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

Key Words: medulloblastoma, epigenetics, hypermethylation, COL1A2, desmoplasia

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