Abstract
BackgroundAbnormal DNA methylation may be important in germ cell tumour (GCT) aetiology, as germ cells undergo complete epigenetic reprogramming during development. GCTs show differences in global and promoter methylation patterns by histologic subtype. We conducted an epigenome-wide study to identify methylation differences by GCT histology.MethodsUsing the Illumina HumanMethylation450K array we measured methylation in 154 paediatric GCTs (21 germinomas/seminomas/dysgerminoma, 70 yolk sac tumours [YST], 9 teratomas, and 54 mixed histology tumours). We identified differentially methylated regions (DMRs) between GCT histologies by comparing methylation beta values.ResultsWe identified 8,481 DMRs (FWER < 0.05). Unsupervised hierarchical clustering of individual probes within DMRs resulted in four high level clusters closely corresponding to tumour histology. Clusters corresponding to age, location, sex and FFPE status were not observed within these DMRs. Germinomas displayed lower levels of methylation across the DMRs relative to the other histologic subtypes. Pathway analysis on the top 10% of genes with differential methylation in germinomas/seminomas/dysgerminoma compared to YST suggested angiogenesis and immune cell-related pathways displayed decreased methylation in germinomas/seminomas/dysgerminoma relative to YST.ConclusionsPaediatric GCT histologies have differential methylation patterns. The genes that are differentially methylated may provide insights into GCT aetiology including the timing of GCT initiation.
Highlights
Germ cell tumours (GCTs), arising from totipotent primordial germ cells (PGC), are histologically heterogeneous tumours found in males and females in both gonadal and extragonadal locations.The main histologic subtypes of germ cell tumour (GCT) in the paediatric and adolescent population include: germinoma arising in the brain, yolk sac tumour (YST), seminoma/dysgerminoma, and teratomas.[1]
76% of both germinomas/seminoma/dysgerminoma and mixed tumours were diagnosed among children aged 11–19 years, teratomas were distributed by age, and 71% of yolk sac tumours (YST) were among children aged 0–10 years (p < 0.01)
Tumour location varied significantly by GCT histologic subtype (p < 0.01) with 58% of germinomas/seminoma/dysgerminoma diagnosed in the ovary, 61% of mixed tumours diagnosed in the testes, teratomas were more evenly distributed among tumour locations, and no YSTs were intracranial but were more frequently gonadal in location
Summary
Germ cell tumours (GCTs), arising from totipotent primordial germ cells (PGC), are histologically heterogeneous tumours found in males and females in both gonadal and extragonadal locations.The main histologic subtypes of GCTs in the paediatric and adolescent population include: germinoma arising in the brain, yolk sac tumour (YST), seminoma/dysgerminoma, and teratomas (mature and immature).[1]. Germ cell tumours (GCTs), arising from totipotent primordial germ cells (PGC), are histologically heterogeneous tumours found in males and females in both gonadal and extragonadal locations. The most common histology among females < 5 years of age is generally YST and/or teratomas, whereas in adolescence, the most common histologic subtypes are dysgerminoma and teratoma.[2] Extragonadal tumours are more common in the paediatric age range compared to adolescent or young adult tumours, and are thought to arise from abnormal migration of PGCs during embryogenesis.[8,9] As germ cells undergo extensive epigenetic reprogramming during the embryonic and early developmental periods,[6,10,11,12] understanding differences in methylation patterns between histologic subtypes may shed light on aetiologic variation by histology as we work toward identifying important windows of exposure. The genes that are differentially methylated may provide insights into GCT aetiology including the timing of GCT initiation
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