TY - JOUR
T1 - Differences in DNA methylation profiles by histologic subtype of paediatric germ cell tumours
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
N1 - Funding Information:
This work was supported by the National Institutes of Health (grant numbers R01 CA151284 to J.N.P.; T32 CA099936 to L.A.W.; NCTN Operations Centre Grant [U10 CA180886]; and NCTN Statistics & Data Centre Grant [U10CA180899]), and the Children’s Cancer Research Fund, Minneapolis, MN.
Publisher Copyright:
© 2018, Cancer Research UK.
PY - 2018/10/2
Y1 - 2018/10/2
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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U2 - 10.1038/s41416-018-0277-5
DO - 10.1038/s41416-018-0277-5
M3 - Article
C2 - 30287918
AN - SCOPUS:85054585809
SN - 0007-0920
VL - 119
SP - 864
EP - 872
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 7
ER -
