Differences in DNA methylation profiles by histologic subtype of paediatric germ cell tumours

a report from the Children’s Oncology Group

Lindsay A. Williams, Lauren J Mills, Anthony J Hooten, Erica K Langer, Michelle Roesler, A. Lindsay Frazier, Mark Krailo, Heather H Nelson, Jessica Bestrashniy, James F. Amatruda, Jenny Poynter

Research output: Contribution to journalArticle

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Abstract

Background: Abnormal 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. Methods: Using 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. Results: We 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. Conclusions: Paediatric GCT histologies have differential methylation patterns. The genes that are differentially methylated may provide insights into GCT aetiology including the timing of GCT initiation.

Original languageEnglish (US)
Pages (from-to)864-872
Number of pages9
JournalBritish Journal of Cancer
Volume119
Issue number7
DOIs
StatePublished - Oct 2 2018

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Germ Cell and Embryonal Neoplasms
DNA Methylation
Methylation
Germinoma
Pediatrics
Dysgerminoma
Histology
Endodermal Sinus Tumor
Seminoma
Teratoma
Epigenomics
Germ Cells
Genes
Cluster Analysis
Neoplasms

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Differences in DNA methylation profiles by histologic subtype of paediatric germ cell tumours : a report from the Children’s Oncology Group. / Williams, Lindsay A.; Mills, Lauren J; Hooten, Anthony J; Langer, Erica K; Roesler, Michelle; Frazier, A. Lindsay; Krailo, Mark; Nelson, Heather H; Bestrashniy, Jessica; Amatruda, James F.; Poynter, Jenny.

In: British Journal of Cancer, Vol. 119, No. 7, 02.10.2018, p. 864-872.

Research output: Contribution to journalArticle

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abstract = "Background: Abnormal 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. Methods: Using 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. Results: We 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. Conclusions: Paediatric GCT histologies have differential methylation patterns. The genes that are differentially methylated may provide insights into GCT aetiology including the timing of GCT initiation.",
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T2 - a report from the Children’s Oncology Group

AU - Williams, Lindsay A.

AU - Mills, Lauren J

AU - Hooten, Anthony J

AU - Langer, Erica K

AU - Roesler, Michelle

AU - Frazier, A. Lindsay

AU - Krailo, Mark

AU - Nelson, Heather H

AU - Bestrashniy, Jessica

AU - Amatruda, James F.

AU - Poynter, Jenny

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N2 - Background: Abnormal 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. Methods: Using 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. Results: We 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. Conclusions: Paediatric GCT histologies have differential methylation patterns. The genes that are differentially methylated may provide insights into GCT aetiology including the timing of GCT initiation.

AB - Background: Abnormal 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. Methods: Using 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. Results: We 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. Conclusions: Paediatric GCT histologies have differential methylation patterns. The genes that are differentially methylated may provide insights into GCT aetiology including the timing of GCT initiation.

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