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Methylator phenotype of malignant germ cell tumours in children identifies strong candidates for chemotherapy resistance

Lookup NU author(s): Dr Ed Schwalbe, Professor Steven CliffordORCiD

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Abstract

BACKGROUND: Yolk sac tumours (YSTs) and germinomas are the two major pure histological subtypes of germ cell tumours. To date, the role of DNA methylation in the aetiology of this class of tumour has only been analysed in adult testicular forms and with respect to only a few genes. METHODS: A bank of paediatric tumours was analysed for global methylation of LINE-1 repeat elements and global methylation of regulatory elements using GoldenGate methylation arrays. RESULTS: Both germinomas and YSTs exhibited significant global hypomethylation of LINE-1 elements. However, in germinomas, methylation of gene regulatory regions differed little from control samples, whereas YSTs exhibited increased methylation at a large proportion of the loci tested, showing a 'methylator' phenotype, including silencing of genes associated with Caspase-8-dependent apoptosis. Furthermore, we found that the methylator phenotype of YSTs was coincident with higher levels of expression of the DNA methyltransferase, DNA (cytosine-5)-methyltransferase 3B, suggesting a mechanism underlying the phenotype. CONCLUSION: Epigenetic silencing of a large number of potential tumour suppressor genes in YSTs might explain why they exhibit a more aggressive natural history than germinomas and silencing of genes associated with Caspase-8-dependent cell death might explain the relative resistance of YSTs to conventional therapy. British Journal of Cancer (2011) 105, 575-585. doi:10.1038/bjc.2011.218 www.bjcancer.com Published online 28 June 2011 (C) 2011 Cancer Research UK

Publication metadata

Author(s): Jeyapalan JN, Noor DAM, Lee SH, Tan CL, Appleby VA, Kilday JP, Palmer RD, Schwalbe EC, Clifford SC, Walker DA, Murray MJ, Coleman N, Nicholson JC, Scotting PJ

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 2011

Volume: 105

Issue: 4

Pages: 575-585

Print publication date: 28/06/2011

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/bjc.2011.218

DOI: 10.1038/bjc.2011.218

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