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Oncotarget. 2015 Mar 30;6(9):7232-43.

Multiple mechanisms of MYCN dysregulation in Wilms tumour.

Author information

1
UCL Institute of Child Health, London, UK.
2
Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry and Comprehensive Cancer Center Mainfranken, Wuerzburg University, Wuerzburg, Germany.
3
Institute of Cancer Research, Sutton, Surrey, UK.
4
Cardiff University School of Medicine, Heath Park, Cardiff, UK.
5
Biometrics Department, Netherlands Cancer Institute, Antonie van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands.
6
Department of Pediatric Oncology/Hematology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
7
German Cancer Research Centre, Heidelberg, Germany.
8
Academic Medical Center, Amsterdam, The Netherlands.
9
Department of Clinical Genetics, Lund University, Sweden.
10
Department of Paediatric Oncology and Haematology, Saarland University Hospital, Homburg/Saar, Germany.

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.

KEYWORDS:

DNA methylation; MYCN; Wilms tumour; copy number; prognostic marker

PMID:
25749049
PMCID:
PMC4466681
DOI:
10.18632/oncotarget.3377
[Indexed for MEDLINE]
Free PMC Article

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