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Genome wide DNA methylation profiles provide clues to the origin and pathogenesis of germ cell tumors.

ABSTRACT: The cell of origin of the five subtypes (I-V) of germ cell tumors (GCTs) are assumed to be germ cells from different maturation stages. This is (potentially) reflected in their methylation status as fetal maturing primordial germ cells are globally demethylated during migration from the yolk sac to the gonad. Imprinted regions are erased in the gonad and later become uniparentally imprinted according to fetal sex. Here, 91 GCTs (type I-IV) and four cell lines were profiled (Illumina's HumanMethylation450BeadChip). Data was pre-processed controlling for cross hybridization, SNPs, detection rate, probe-type bias and batch effects. The annotation was extended, covering snRNAs/microRNAs, repeat elements and imprinted regions. A Hidden Markov Model-based genome segmentation was devised to identify differentially methylated genomic regions. Methylation profiles allowed for separation of clusters of non-seminomas (type II), seminomas/dysgerminomas (type II), spermatocytic seminomas (type III) and teratomas/dermoid cysts (type I/IV). The seminomas, dysgerminomas and spermatocytic seminomas were globally hypomethylated, in line with previous reports and their demethylated precursor. Differential methylation and imprinting status between subtypes reflected their presumed cell of origin. Ovarian type I teratomas and dermoid cysts showed (partial) sex specific uniparental maternal imprinting. The spermatocytic seminomas showed uniparental paternal imprinting while testicular teratomas exhibited partial imprinting erasure. Somatic imprinting in type II GCTs might indicate a cell of origin after global demethylation but before imprinting erasure. This is earlier than previously described, but agrees with the totipotent/embryonic stem cell like potential of type II GCTs and their rare extra-gonadal localization. The results support the common origin of the type I teratomas and show strong similarity between ovarian type I teratomas and dermoid cysts. In conclusion, we identified specific and global methylation differences between GCT subtypes, providing insight into their developmental timing and underlying developmental biology. Data and extended annotation are deposited at GEO (GSE58538 and GPL18809).

SUBMITTER: Rijlaarsdam MA

PROVIDER: S-EPMC4479500 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Genome wide DNA methylation profiles provide clues to the origin and pathogenesis of germ cell tumors.

Rijlaarsdam Martin A MA Tax David M J DM Gillis Ad J M AJ Dorssers Lambert C J LC Koestler Devin C DC de Ridder Jeroen J Looijenga Leendert H J LH

PloS one 20150410 4

The cell of origin of the five subtypes (I-V) of germ cell tumors (GCTs) are assumed to be germ cells from different maturation stages. This is (potentially) reflected in their methylation status as fetal maturing primordial germ cells are globally demethylated during migration from the yolk sac to the gonad. Imprinted regions are erased in the gonad and later become uniparentally imprinted according to fetal sex. Here, 91 GCTs (type I-IV) and four cell lines were profiled (Illumina's HumanMethy ...[more]

PMID: 25859847

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Project description:Germ cell tumors (GCT) originate from germ cells at different developmental stages (GCT type I – V) They are thought to inherit their methylation profile from (early embryonic) germ cells which undergo a characteristic epigenetic “reset” during maturation. This study aims to provide insight into the developmental timing and underlying biology of the various subtypes of GCTs and their (embryonic) cells of origin by identifying specific and global methylation differences between GCT subtypes. In total, 91 type I-IV GCTs and four cell lines were profiled using the Illumina HumanMethylation450 BeadChip (450K) platform. The data were pre-processed using a validated pipeline and analyzed using an in-house generated extension of the annotation manifest. Marked methylation differences were identified between GCT subtypes both on the global and local level (i.e. differentially methylated regions, imprinting control regions, promoters, etc). GCT subtypes indeed show major similarities to specific stages of (early) developing embryonic germ cells with regard to their methylation profile. The extended annotation manifest for the Illumina 450K platform and methylation datasets are readily available on GEO (GEO accession: GSE58538, GPL18809), providing an integrated hypothesis generating data source for future research. 91 germ cell tumors of various histologies were investigated for their methylation profile. Methylation detection was performed using Illumina’s HumanMethylation450 BeadChip. 14 type I teratomas (TE) were included of which 6 were located sacral (3 male: I.TE.s.m; 3 female: I.TE.s.f), 4 were located in the testis (I.TE.t) and 3 were located in the ovary (I.TE.o). 30 pure embryonal carcinomas (EC) were included as well as 21 mixed non seminomas (mNS). 12 seminomas of the testis (SE) were included as well as 4 dysgerminomas (their couterpart in the ovary). Finally, 4 spermatocytic seminomas (SS) and three dermoid cysts were analyzed. For a detailed overview the histological classification of germ cell tumors please see the publication linked to this data or associated literature [1-3]. Four cell lines were included, al modelling type II GCTs. Cell lines derived from EC include NT2[4-8], NCCIT [5, 9] and 2102EP[4-8]. TCam-2 closely resembles SE [10-12]. 1. Oosterhuis, J.W. and L.H. Looijenga, Testicular germ-cell tumours in a broader perspective. Nat Rev Cancer, 2005. 5(3): p. 210-22. 2. Looijenga, L.H., Human testicular (non)seminomatous germ cell tumours: the clinical implications of recent pathobiological insights. J Pathol, 2009. 218(2): p. 146-62. 3. Woodward, P.J., et al., Testicular germ cell tumors, in World Health Organization Classification of Tumours Pathology and Genetics of the Urinary System and Male Genital Organs., J.N. Eble, et al., Editors. 2004, IARC Press: Lyon. p. 17-278. 4. Andrews, P.W., et al., A comparative study of eight cell lines derived from human testicular teratocarcinoma. Int J Cancer, 1980. 26(3): p. 269-80. 5. Andrews, P.W., et al., Comparative analysis of cell surface antigens expressed by cell lines derived from human germ cell tumours. Int J Cancer, 1996. 66(6): p. 806-16. 6. Wang, N., et al., Nonrandom abnormalities in chromosome 1 in human testicular cancers. Cancer Res, 1980. 40(3): p. 796-802. 7. Fogh, J. and G. Trempe, New Human Tumor Cell Lines, in Human Tumor Cells in Vitro, J. Fogh, Editor. 1975, Springer US. p. 115-159. 8. Fogh, J., Cultivation, characterization, and identification of human tumor cells with emphasis on kidney, testis, and bladder tumors. Natl Cancer Inst Monogr, 1978(49): p. 5-9. 9. Teshima, S., et al., Four new human germ cell tumor cell lines. Lab Invest, 1988. 59(3): p. 328-36. 10. Eckert, D., et al., TCam-2 but not JKT-1 cells resemble seminoma in cell culture. Cell Tissue Res, 2008. 331(2): p. 529-38. 11. de Jong, J., et al., Further characterization of the first seminoma cell line TCam-2. Genes Chromosomes Cancer, 2008. 47(3): p. 185-96. 12. Mizuno, Y., et al., [Establishment and characterization of a new human testicular germ cell tumor cell line (TCam-2)]. Nihon Hinyokika Gakkai Zasshi, 1993. 84(7): p. 1211-8.

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Genome wide DNA methylation profiles provide clues to the origin and pathogenesis of germ cell tumors.

Publications

Genome wide DNA methylation profiles provide clues to the origin and pathogenesis of germ cell tumors.

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