title: Methylator phenotype of malignant germ cell tumours in children identifies strong candidates for chemotherapy resistance.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Children's Brain Tumour Research Centre, Centre for Genetics and Genomics, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: J N
authors.initials: JN
authors.lastname: Jeyapalan
authors.forename: D A Mohamed
authors.initials: DA
authors.lastname: Noor
authors.forename: S-H
authors.initials: SH
authors.lastname: Lee
authors.forename: C L
authors.initials: CL
authors.lastname: Tan
authors.forename: V A
authors.initials: VA
authors.lastname: Appleby
authors.forename: J P
authors.initials: JP
authors.lastname: Kilday
authors.forename: R D
authors.initials: RD
authors.lastname: Palmer
authors.forename: E C
authors.initials: EC
authors.lastname: Schwalbe
authors.forename: S C
authors.initials: SC
authors.lastname: Clifford
authors.forename: D A
authors.initials: DA
authors.lastname: Walker
authors.forename: M J
authors.initials: MJ
authors.lastname: Murray
authors.forename: N
authors.initials: N
authors.lastname: Coleman
authors.forename: J C
authors.initials: JC
authors.lastname: Nicholson
authors.forename: P J
authors.initials: PJ
authors.lastname: Scotting
mesh_terms: D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D018240:Endodermal Sinus Tumor / Q000188:drug therapy / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D018237:Germinoma / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097584:DNA Methyltransferase 3B
chemical_list: D053181:Caspase 8; D004248:DNA (Cytosine-5-)-Methyltransferases; D000097584:DNA Methyltransferase 3B