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

Authors :
Jeyapalan, J. N.
Noor, D. A. Mohamed
Lee, S.-H.
Tan, C. L.
Appleby, V. A.
Kilday, J. P.
Palmer, R. D.
Schwalbe, E. C.
Clifford, S. C.
Walker, D. A.
Murray, M. J.
Coleman, N.
Nicholson, J. C.
Scotting, P. J.
Source :
British Journal of Cancer; 8/9/2011, Vol. 105 Issue 4, p575-585, 11p, 1 Diagram, 3 Charts, 4 Graphs
Publication Year :
2011

Abstract

<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00070920
Volume :
105
Issue :
4
Database :
Complementary Index
Journal :
British Journal of Cancer
Publication Type :
Academic Journal
Accession number :
64003027
Full Text :
https://doi.org/10.1038/bjc.2011.218