Genome-wide methylation analyses in glioblastoma multiforme.
Few studies had investigated genome-wide methylation in glioblastoma multiforme (GBM). Our goals were to study differential methylation across the genome in gene promoters using an array-based method, as well as repetitive elements using surrogate global methylation markers. The discovery sample set...
Main Authors: | , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2014-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC3931727?pdf=render |
_version_ | 1811319938978152448 |
---|---|
author | Rose K Lai Yanwen Chen Xiaowei Guan Darryl Nousome Charu Sharma Peter Canoll Jeffrey Bruce Andrew E Sloan Etty Cortes Jean-Paul Vonsattel Tao Su Lissette Delgado-Cruzata Irina Gurvich Regina M Santella Quinn Ostrom Annette Lee Peter Gregersen Jill Barnholtz-Sloan |
author_facet | Rose K Lai Yanwen Chen Xiaowei Guan Darryl Nousome Charu Sharma Peter Canoll Jeffrey Bruce Andrew E Sloan Etty Cortes Jean-Paul Vonsattel Tao Su Lissette Delgado-Cruzata Irina Gurvich Regina M Santella Quinn Ostrom Annette Lee Peter Gregersen Jill Barnholtz-Sloan |
author_sort | Rose K Lai |
collection | DOAJ |
description | Few studies had investigated genome-wide methylation in glioblastoma multiforme (GBM). Our goals were to study differential methylation across the genome in gene promoters using an array-based method, as well as repetitive elements using surrogate global methylation markers. The discovery sample set for this study consisted of 54 GBM from Columbia University and Case Western Reserve University, and 24 brain controls from the New York Brain Bank. We assembled a validation dataset using methylation data of 162 TCGA GBM and 140 brain controls from dbGAP. HumanMethylation27 Analysis Bead-Chips (Illumina) were used to interrogate 26,486 informative CpG sites in both the discovery and validation datasets. Global methylation levels were assessed by analysis of L1 retrotransposon (LINE1), 5 methyl-deoxycytidine (5m-dC) and 5 hydroxylmethyl-deoxycytidine (5hm-dC) in the discovery dataset. We validated a total of 1548 CpG sites (1307 genes) that were differentially methylated in GBM compared to controls. There were more than twice as many hypomethylated genes as hypermethylated ones. Both the discovery and validation datasets found 5 tumor methylation classes. Pathway analyses showed that the top ten pathways in hypomethylated genes were all related to functions of innate and acquired immunities. Among hypermethylated pathways, transcriptional regulatory network in embryonic stem cells was the most significant. In the study of global methylation markers, 5m-dC level was the best discriminant among methylation classes, whereas in survival analyses, high level of LINE1 methylation was an independent, favorable prognostic factor in the discovery dataset. Based on a pathway approach, hypermethylation in genes that control stem cell differentiation were significant, poor prognostic factors of overall survival in both the discovery and validation datasets. Approaches that targeted these methylated genes may be a future therapeutic goal. |
first_indexed | 2024-04-13T12:51:08Z |
format | Article |
id | doaj.art-5272d5c08b314dfeba165348f82de440 |
institution | Directory Open Access Journal |
issn | 1932-6203 |
language | English |
last_indexed | 2024-04-13T12:51:08Z |
publishDate | 2014-01-01 |
publisher | Public Library of Science (PLoS) |
record_format | Article |
series | PLoS ONE |
spelling | doaj.art-5272d5c08b314dfeba165348f82de4402022-12-22T02:46:12ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0192e8937610.1371/journal.pone.0089376Genome-wide methylation analyses in glioblastoma multiforme.Rose K LaiYanwen ChenXiaowei GuanDarryl NousomeCharu SharmaPeter CanollJeffrey BruceAndrew E SloanEtty CortesJean-Paul VonsattelTao SuLissette Delgado-CruzataIrina GurvichRegina M SantellaQuinn OstromAnnette LeePeter GregersenJill Barnholtz-SloanFew studies had investigated genome-wide methylation in glioblastoma multiforme (GBM). Our goals were to study differential methylation across the genome in gene promoters using an array-based method, as well as repetitive elements using surrogate global methylation markers. The discovery sample set for this study consisted of 54 GBM from Columbia University and Case Western Reserve University, and 24 brain controls from the New York Brain Bank. We assembled a validation dataset using methylation data of 162 TCGA GBM and 140 brain controls from dbGAP. HumanMethylation27 Analysis Bead-Chips (Illumina) were used to interrogate 26,486 informative CpG sites in both the discovery and validation datasets. Global methylation levels were assessed by analysis of L1 retrotransposon (LINE1), 5 methyl-deoxycytidine (5m-dC) and 5 hydroxylmethyl-deoxycytidine (5hm-dC) in the discovery dataset. We validated a total of 1548 CpG sites (1307 genes) that were differentially methylated in GBM compared to controls. There were more than twice as many hypomethylated genes as hypermethylated ones. Both the discovery and validation datasets found 5 tumor methylation classes. Pathway analyses showed that the top ten pathways in hypomethylated genes were all related to functions of innate and acquired immunities. Among hypermethylated pathways, transcriptional regulatory network in embryonic stem cells was the most significant. In the study of global methylation markers, 5m-dC level was the best discriminant among methylation classes, whereas in survival analyses, high level of LINE1 methylation was an independent, favorable prognostic factor in the discovery dataset. Based on a pathway approach, hypermethylation in genes that control stem cell differentiation were significant, poor prognostic factors of overall survival in both the discovery and validation datasets. Approaches that targeted these methylated genes may be a future therapeutic goal.http://europepmc.org/articles/PMC3931727?pdf=render |
spellingShingle | Rose K Lai Yanwen Chen Xiaowei Guan Darryl Nousome Charu Sharma Peter Canoll Jeffrey Bruce Andrew E Sloan Etty Cortes Jean-Paul Vonsattel Tao Su Lissette Delgado-Cruzata Irina Gurvich Regina M Santella Quinn Ostrom Annette Lee Peter Gregersen Jill Barnholtz-Sloan Genome-wide methylation analyses in glioblastoma multiforme. PLoS ONE |
title | Genome-wide methylation analyses in glioblastoma multiforme. |
title_full | Genome-wide methylation analyses in glioblastoma multiforme. |
title_fullStr | Genome-wide methylation analyses in glioblastoma multiforme. |
title_full_unstemmed | Genome-wide methylation analyses in glioblastoma multiforme. |
title_short | Genome-wide methylation analyses in glioblastoma multiforme. |
title_sort | genome wide methylation analyses in glioblastoma multiforme |
url | http://europepmc.org/articles/PMC3931727?pdf=render |
work_keys_str_mv | AT roseklai genomewidemethylationanalysesinglioblastomamultiforme AT yanwenchen genomewidemethylationanalysesinglioblastomamultiforme AT xiaoweiguan genomewidemethylationanalysesinglioblastomamultiforme AT darrylnousome genomewidemethylationanalysesinglioblastomamultiforme AT charusharma genomewidemethylationanalysesinglioblastomamultiforme AT petercanoll genomewidemethylationanalysesinglioblastomamultiforme AT jeffreybruce genomewidemethylationanalysesinglioblastomamultiforme AT andrewesloan genomewidemethylationanalysesinglioblastomamultiforme AT ettycortes genomewidemethylationanalysesinglioblastomamultiforme AT jeanpaulvonsattel genomewidemethylationanalysesinglioblastomamultiforme AT taosu genomewidemethylationanalysesinglioblastomamultiforme AT lissettedelgadocruzata genomewidemethylationanalysesinglioblastomamultiforme AT irinagurvich genomewidemethylationanalysesinglioblastomamultiforme AT reginamsantella genomewidemethylationanalysesinglioblastomamultiforme AT quinnostrom genomewidemethylationanalysesinglioblastomamultiforme AT annettelee genomewidemethylationanalysesinglioblastomamultiforme AT petergregersen genomewidemethylationanalysesinglioblastomamultiforme AT jillbarnholtzsloan genomewidemethylationanalysesinglioblastomamultiforme |