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Global DNA methylation in fetal human germ cells and germ cell tumours: association with differentiation and cisplatin resistance
Author(s) -
Wermann Hendrik,
Stoop Hans,
Gillis Ad JM,
Honecker Friedemann,
van Gurp Ruud JHLM,
Ammerpohl Ole,
Richter Julia,
Oosterhuis J Wolter,
Bokemeyer Carsten,
Looijenga Leendert HJ
Publication year - 2010
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2725
Subject(s) - dna methylation , methylation , biology , cancer research , germ cell , germ cell tumors , testicular germ cell tumor , yolk sac , homeobox protein nanog , seminoma , microbiology and biotechnology , pathology , genetics , embryonic stem cell , gene expression , gene , medicine , embryo , chemotherapy , induced pluripotent stem cell
Abstract 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‐ $^{\rm m}$ 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. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.