Multiple mechanisms of MYCN dysregulation in Wilms tumour

Richard D. Williams, Tasnim Chagtai, Marisa Alcaide-German, John Apps, Jenny Wegert, Sergey Popov, Gordan Vujanic, van Tinteren Harm van Tinteren, Marry M. van den Heuvel-Eibrink, Marcel Kool, de Kraker Jan de Kraker, David Gisselsson, Norbert Graf, Manfred Gessler, Kathy Pritchard-Jones

Research output: Contribution to journalArticlepeer-review

79 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)7232-7243
Number of pages12
Issue number9
Publication statusPublished - 2015
Externally publishedYes


  • Copy number
  • DNA methylation
  • MYCN
  • Prognostic marker
  • Wilms tumour


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