Cargando…
Widespread Dysregulation of MiRNAs by MYCN Amplification and Chromosomal Imbalances in Neuroblastoma: Association of miRNA Expression with Survival
MiRNAs regulate gene expression at a post-transcriptional level and their dysregulation can play major roles in the pathogenesis of many different forms of cancer, including neuroblastoma, an often fatal paediatric cancer originating from precursor cells of the sympathetic nervous system. We have an...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2009
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773120/ https://www.ncbi.nlm.nih.gov/pubmed/19924232 http://dx.doi.org/10.1371/journal.pone.0007850 |
_version_ | 1782173847516086272 |
---|---|
author | Bray, Isabella Bryan, Kenneth Prenter, Suzanne Buckley, Patrick G. Foley, Niamh H. Murphy, Derek M. Alcock, Leah Mestdagh, Pieter Vandesompele, Jo Speleman, Frank London, Wendy B. McGrady, Patrick W. Higgins, Desmond G. O'Meara, Anne O'Sullivan, Maureen Stallings, Raymond L. |
author_facet | Bray, Isabella Bryan, Kenneth Prenter, Suzanne Buckley, Patrick G. Foley, Niamh H. Murphy, Derek M. Alcock, Leah Mestdagh, Pieter Vandesompele, Jo Speleman, Frank London, Wendy B. McGrady, Patrick W. Higgins, Desmond G. O'Meara, Anne O'Sullivan, Maureen Stallings, Raymond L. |
author_sort | Bray, Isabella |
collection | PubMed |
description | MiRNAs regulate gene expression at a post-transcriptional level and their dysregulation can play major roles in the pathogenesis of many different forms of cancer, including neuroblastoma, an often fatal paediatric cancer originating from precursor cells of the sympathetic nervous system. We have analyzed a set of neuroblastoma (n = 145) that is broadly representative of the genetic subtypes of this disease for miRNA expression (430 loci by stem-loop RT qPCR) and for DNA copy number alterations (array CGH) to assess miRNA involvement in disease pathogenesis. The tumors were stratified and then randomly split into a training set (n = 96) and a validation set (n = 49) for data analysis. Thirty-seven miRNAs were significantly over- or under-expressed in MYCN amplified tumors relative to MYCN single copy tumors, indicating a potential role for the MYCN transcription factor in either the direct or indirect dysregulation of these loci. In addition, we also determined that there was a highly significant correlation between miRNA expression levels and DNA copy number, indicating a role for large-scale genomic imbalances in the dysregulation of miRNA expression. In order to directly assess whether miRNA expression was predictive of clinical outcome, we used the Random Forest classifier to identify miRNAs that were most significantly associated with poor overall patient survival and developed a 15 miRNA signature that was predictive of overall survival with 72.7% sensitivity and 86.5% specificity in the validation set of tumors. We conclude that there is widespread dysregulation of miRNA expression in neuroblastoma tumors caused by both over-expression of the MYCN transcription factor and by large-scale chromosomal imbalances. MiRNA expression patterns are also predicative of clinical outcome, highlighting the potential for miRNA mediated diagnostics and therapeutics. |
format | Text |
id | pubmed-2773120 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-27731202009-11-19 Widespread Dysregulation of MiRNAs by MYCN Amplification and Chromosomal Imbalances in Neuroblastoma: Association of miRNA Expression with Survival Bray, Isabella Bryan, Kenneth Prenter, Suzanne Buckley, Patrick G. Foley, Niamh H. Murphy, Derek M. Alcock, Leah Mestdagh, Pieter Vandesompele, Jo Speleman, Frank London, Wendy B. McGrady, Patrick W. Higgins, Desmond G. O'Meara, Anne O'Sullivan, Maureen Stallings, Raymond L. PLoS One Research Article MiRNAs regulate gene expression at a post-transcriptional level and their dysregulation can play major roles in the pathogenesis of many different forms of cancer, including neuroblastoma, an often fatal paediatric cancer originating from precursor cells of the sympathetic nervous system. We have analyzed a set of neuroblastoma (n = 145) that is broadly representative of the genetic subtypes of this disease for miRNA expression (430 loci by stem-loop RT qPCR) and for DNA copy number alterations (array CGH) to assess miRNA involvement in disease pathogenesis. The tumors were stratified and then randomly split into a training set (n = 96) and a validation set (n = 49) for data analysis. Thirty-seven miRNAs were significantly over- or under-expressed in MYCN amplified tumors relative to MYCN single copy tumors, indicating a potential role for the MYCN transcription factor in either the direct or indirect dysregulation of these loci. In addition, we also determined that there was a highly significant correlation between miRNA expression levels and DNA copy number, indicating a role for large-scale genomic imbalances in the dysregulation of miRNA expression. In order to directly assess whether miRNA expression was predictive of clinical outcome, we used the Random Forest classifier to identify miRNAs that were most significantly associated with poor overall patient survival and developed a 15 miRNA signature that was predictive of overall survival with 72.7% sensitivity and 86.5% specificity in the validation set of tumors. We conclude that there is widespread dysregulation of miRNA expression in neuroblastoma tumors caused by both over-expression of the MYCN transcription factor and by large-scale chromosomal imbalances. MiRNA expression patterns are also predicative of clinical outcome, highlighting the potential for miRNA mediated diagnostics and therapeutics. Public Library of Science 2009-11-16 /pmc/articles/PMC2773120/ /pubmed/19924232 http://dx.doi.org/10.1371/journal.pone.0007850 Text en Bray et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Bray, Isabella Bryan, Kenneth Prenter, Suzanne Buckley, Patrick G. Foley, Niamh H. Murphy, Derek M. Alcock, Leah Mestdagh, Pieter Vandesompele, Jo Speleman, Frank London, Wendy B. McGrady, Patrick W. Higgins, Desmond G. O'Meara, Anne O'Sullivan, Maureen Stallings, Raymond L. Widespread Dysregulation of MiRNAs by MYCN Amplification and Chromosomal Imbalances in Neuroblastoma: Association of miRNA Expression with Survival |
title | Widespread Dysregulation of MiRNAs by MYCN Amplification and Chromosomal Imbalances in Neuroblastoma: Association of miRNA Expression with Survival |
title_full | Widespread Dysregulation of MiRNAs by MYCN Amplification and Chromosomal Imbalances in Neuroblastoma: Association of miRNA Expression with Survival |
title_fullStr | Widespread Dysregulation of MiRNAs by MYCN Amplification and Chromosomal Imbalances in Neuroblastoma: Association of miRNA Expression with Survival |
title_full_unstemmed | Widespread Dysregulation of MiRNAs by MYCN Amplification and Chromosomal Imbalances in Neuroblastoma: Association of miRNA Expression with Survival |
title_short | Widespread Dysregulation of MiRNAs by MYCN Amplification and Chromosomal Imbalances in Neuroblastoma: Association of miRNA Expression with Survival |
title_sort | widespread dysregulation of mirnas by mycn amplification and chromosomal imbalances in neuroblastoma: association of mirna expression with survival |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773120/ https://www.ncbi.nlm.nih.gov/pubmed/19924232 http://dx.doi.org/10.1371/journal.pone.0007850 |
work_keys_str_mv | AT brayisabella widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival AT bryankenneth widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival AT prentersuzanne widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival AT buckleypatrickg widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival AT foleyniamhh widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival AT murphyderekm widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival AT alcockleah widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival AT mestdaghpieter widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival AT vandesompelejo widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival AT spelemanfrank widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival AT londonwendyb widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival AT mcgradypatrickw widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival AT higginsdesmondg widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival AT omearaanne widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival AT osullivanmaureen widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival AT stallingsraymondl widespreaddysregulationofmirnasbymycnamplificationandchromosomalimbalancesinneuroblastomaassociationofmirnaexpressionwithsurvival |