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Multiple mechanisms of MYCN dysregulation in Wilms tumour.

Williams, Richard D ; Chagtai, Tasnim ; Alcaide-German, Marisa ; Apps, John ; Wegert, Jenny ; Popov, Sergey ; Vujanic, Gordan ; van Tinteren, Harm ; van den Heuvel-Eibrink, Marry M and Kool, Marcel , et al. (2015) In Oncotarget 6(9). p.7232-7243
Abstract
Genomic gain of the proto-oncogene transcription factor gene MYCN is associated with poor prognosis in several childhood cancers. Here we present a comprehensive copy number analysis of MYCN in Wilms tumour (WT), demonstrating that gain of this gene is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. Using whole exome and gene-specific sequencing, together with methylation and expression profiling, we show that MYCN is targeted by other mechanisms, including a recurrent somatic mutation, P44L, and specific DNA hypomethylation events associated with MYCN overexpression in tumours with high risk histologies. We describe parallel evolution of genomic copy number gain and point mutation of... (More)
Genomic gain of the proto-oncogene transcription factor gene MYCN is associated with poor prognosis in several childhood cancers. Here we present a comprehensive copy number analysis of MYCN in Wilms tumour (WT), demonstrating that gain of this gene is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. Using whole exome and gene-specific sequencing, together with methylation and expression profiling, we show that MYCN is targeted by other mechanisms, including a recurrent somatic mutation, P44L, and specific DNA hypomethylation events associated with MYCN overexpression in tumours with high risk histologies. We describe parallel evolution of genomic copy number gain and point mutation of MYCN in the contralateral tumours of a remarkable bilateral case in which independent contralateral mutations of TP53 also evolve over time. We report a second bilateral case in which MYCN gain is a germline aberration. Our results suggest a significant role for MYCN dysregulation in the molecular biology of Wilms tumour. We conclude that MYCN gain is prognostically significant, and suggest that the novel P44L somatic variant is likely to be an activating mutation. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Oncotarget
volume
6
issue
9
pages
7232 - 7243
publisher
Impact Journals
external identifiers
  • pmid:25749049
  • wos:000352793800055
  • scopus:84924682507
ISSN
1949-2553
language
English
LU publication?
yes
id
71c1ba45-748d-407b-be3d-343de8a815ec (old id 5265054)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25749049?dopt=Abstract
date added to LUP
2016-04-01 13:10:44
date last changed
2022-04-13 23:46:11
@article{71c1ba45-748d-407b-be3d-343de8a815ec,
  abstract     = {{Genomic gain of the proto-oncogene transcription factor gene MYCN is associated with poor prognosis in several childhood cancers. Here we present a comprehensive copy number analysis of MYCN in Wilms tumour (WT), demonstrating that gain of this gene is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. Using whole exome and gene-specific sequencing, together with methylation and expression profiling, we show that MYCN is targeted by other mechanisms, including a recurrent somatic mutation, P44L, and specific DNA hypomethylation events associated with MYCN overexpression in tumours with high risk histologies. We describe parallel evolution of genomic copy number gain and point mutation of MYCN in the contralateral tumours of a remarkable bilateral case in which independent contralateral mutations of TP53 also evolve over time. We report a second bilateral case in which MYCN gain is a germline aberration. Our results suggest a significant role for MYCN dysregulation in the molecular biology of Wilms tumour. We conclude that MYCN gain is prognostically significant, and suggest that the novel P44L somatic variant is likely to be an activating mutation.}},
  author       = {{Williams, Richard D and Chagtai, Tasnim and Alcaide-German, Marisa and Apps, John and Wegert, Jenny and Popov, Sergey and Vujanic, Gordan and van Tinteren, Harm and van den Heuvel-Eibrink, Marry M and Kool, Marcel and de Kraker, Jan and Gisselsson Nord, David and Graf, Norbert and Gessler, Manfred and Pritchard-Jones, Kathy}},
  issn         = {{1949-2553}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{7232--7243}},
  publisher    = {{Impact Journals}},
  series       = {{Oncotarget}},
  title        = {{Multiple mechanisms of MYCN dysregulation in Wilms tumour.}},
  url          = {{https://lup.lub.lu.se/search/files/3206935/8055119.pdf}},
  volume       = {{6}},
  year         = {{2015}},
}