Genome wide DNA methylation profiles provide clues to the origin and pathogenesis of germ cell tumors.
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...
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| Format: | Article |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4479500?pdf=render |
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| author | Martin A Rijlaarsdam David M J Tax Ad J M Gillis Lambert C J Dorssers Devin C Koestler Jeroen de Ridder Leendert H J Looijenga |
| author_facet | Martin A Rijlaarsdam David M J Tax Ad J M Gillis Lambert C J Dorssers Devin C Koestler Jeroen de Ridder Leendert H J Looijenga |
| author_sort | Martin A Rijlaarsdam |
| collection | DOAJ |
| description | 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). |
| first_indexed | 2024-12-12T19:50:46Z |
| format | Article |
| id | doaj.art-975d06688b5f45f1be1ab937fde9af10 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T19:50:46Z |
| publishDate | 2015-01-01 |
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| spelling | doaj.art-975d06688b5f45f1be1ab937fde9af102022-12-22T00:13:58ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01104e012214610.1371/journal.pone.0122146Genome wide DNA methylation profiles provide clues to the origin and pathogenesis of germ cell tumors.Martin A RijlaarsdamDavid M J TaxAd J M GillisLambert C J DorssersDevin C KoestlerJeroen de RidderLeendert H J LooijengaThe 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).http://europepmc.org/articles/PMC4479500?pdf=render |
| spellingShingle | Martin A Rijlaarsdam David M J Tax Ad J M Gillis Lambert C J Dorssers Devin C Koestler Jeroen de Ridder Leendert H J Looijenga Genome wide DNA methylation profiles provide clues to the origin and pathogenesis of germ cell tumors. PLoS ONE |
| title | Genome wide DNA methylation profiles provide clues to the origin and pathogenesis of germ cell tumors. |
| title_full | Genome wide DNA methylation profiles provide clues to the origin and pathogenesis of germ cell tumors. |
| title_fullStr | Genome wide DNA methylation profiles provide clues to the origin and pathogenesis of germ cell tumors. |
| title_full_unstemmed | Genome wide DNA methylation profiles provide clues to the origin and pathogenesis of germ cell tumors. |
| title_short | Genome wide DNA methylation profiles provide clues to the origin and pathogenesis of germ cell tumors. |
| title_sort | genome wide dna methylation profiles provide clues to the origin and pathogenesis of germ cell tumors |
| url | http://europepmc.org/articles/PMC4479500?pdf=render |
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