10779/rcsi.10767908.v1
Isabella Bray
Isabella
Bray
Kenneth Bryan
Kenneth
Bryan
Suzanne Prenter
Suzanne
Prenter
Patrick G. Buckley
Patrick G.
Buckley
Niamh H. Foley
Niamh H.
Foley
Derek M. Murphy
Derek M.
Murphy
Leah Alcock
Leah
Alcock
Pieter Mestdagh
Pieter
Mestdagh
Jo Vandesompele
Jo
Vandesompele
Frank Speleman
Frank
Speleman
Wendy B. London
Wendy B.
London
Patrick W. McGrady
Patrick W.
McGrady
Desmond G. Higgins
Desmond G.
Higgins
Anne O'Meara
Anne
O'Meara
Maureen O'Sullivan
Maureen
O'Sullivan
Raymond L. Stallings
Raymond L.
Stallings
Widespread dysregulation of MiRNAs by MYCN amplification and chromosomal imbalances in neuroblastoma: association of miRNA expression with survival.
Royal College of Surgeons in Ireland
2019
Cell Line
Tumor
Chromosome Aberrations
Cluster Analysis
Cohort Studies
Gene Expression Regulation
Neoplastic
Humans
MicroRNAs/metabolism
Nervous System Neoplasms/genetics/metabolism
Neuroblastoma/*genetics
Nuclear Proteins/*biosynthesis/*genetics
Nucleic Acid Hybridization
Oncogene Proteins/*biosynthesis/*genetics
Reverse Transcriptase Polymerase Chain Reaction
Sensitivity and Specificity
Sequence Analysis
DNA
Sympathetic Nervous System/pathology
Treatment Outcome
Cancer Genetics
2019-11-22 15:17:52
Journal contribution
https://repository.rcsi.com/articles/journal_contribution/Widespread_dysregulation_of_MiRNAs_by_MYCN_amplification_and_chromosomal_imbalances_in_neuroblastoma_association_of_miRNA_expression_with_survival_/10767908
<p>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.</p>