1. Methylator phenotype of malignant germ cell tumours in children identifies strong candidates for chemotherapy resistance.
- Author
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Jeyapalan JN, Noor DA, Lee SH, Tan CL, Appleby VA, Kilday JP, Palmer RD, Schwalbe EC, Clifford SC, Walker DA, Murray MJ, Coleman N, Nicholson JC, and Scotting PJ
- Subjects
- Apoptosis, Child, Child, Preschool, Cluster Analysis, Drug Resistance, Neoplasm, Endodermal Sinus Tumor drug therapy, Endodermal Sinus Tumor genetics, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Germinoma drug therapy, Germinoma genetics, Humans, Male, Microarray Analysis, Neoplasms, Germ Cell and Embryonal pathology, Phenotype, Polymerase Chain Reaction, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, DNA Methyltransferase 3B, Caspase 8 metabolism, DNA (Cytosine-5-)-Methyltransferases metabolism, DNA Methylation, Gene Silencing, Genes, Tumor Suppressor, Neoplasms, Germ Cell and Embryonal drug therapy, Neoplasms, Germ Cell and Embryonal genetics
- 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.
- Published
- 2011
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