Global DNA methylation in fetal human germ cells and germ cell tumours: association with differentiation and cisplatin resistance

Hendrik Wermann, Hans Stoop, Ad J M Gillis, Friedemann Honecker, Ruud J H L M van Gurp, Ole Ammerpohl, Julia Richter, J Wolter Oosterhuis, Carsten Bokemeyer, Leendert H J Looijenga

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154 Citaten (Scopus)


Differences in the global methylation pattern, ie hyper- as well as hypo-methylation, are observed in cancers including germ cell tumours (GCTs). Related to their precursor cells, GCT methylation status differs according to histology. We investigated the methylation pattern of normal fetal, infantile, and adult germ cells (n = 103) and GCTs (n = 251) by immunohistochemical staining for 5-(m)cytidine. The global methylation pattern of male germ cells changes from hypomethylation to hypermethylation, whereas female germ cells remain unmethylated at all stages. Undifferentiated GCTs (seminomas, intratubular germ cell neoplasia unclassified, and gonadoblastomas) are hypomethylated, whereas more differentiated GCTs (teratomas, yolk sac tumours, and choriocarcinomas) show a higher degree of methylation. Embryonal carcinomas show an intermediate pattern. Resistance to cisplatin was assessed in the seminomatous cell line TCam-2 before and after demethylation using 5-azacytidine. Exposure to 5-azacytidine resulted in decreased resistance to cisplatin. Furthermore, after demethylation, the stem cell markers NANOG and POU5F1 (OCT3/4), as well as the germ cell-specific marker VASA, showed increased expression. Following treatment with 5-azacytidine, TCam-2 cells were analysed using a high-throughput methylation screen for changes in the methylation sites of 14,000 genes. Among the genes revealing changes, interesting targets were identified: ie demethylation of KLF11, a putative tumour suppressor gene, and hypermethylation of CFLAR, a gene previously described in treatment resistance in GCTs.

Originele taal-2Engels
Pagina's (van-tot)433-42
Aantal pagina's10
TijdschriftThe Journal of pathology
Nummer van het tijdschrift4
StatusGepubliceerd - aug. 2010
Extern gepubliceerdJa


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