Oncotarget

Research Papers:

Multiple mechanisms of MYCN dysregulation in Wilms tumour

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

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Oncotarget. 2015; 6:7232-7243. https://doi.org/10.18632/oncotarget.3377

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Abstract

Richard D. Williams1, Tasnim Chagtai1, Marisa Alcaide-German1, John Apps1, Jenny Wegert2, Sergey Popov3, Gordan Vujanic4, Harm van Tinteren5, Marry M. van den Heuvel-Eibrink6, Marcel Kool7, Jan de Kraker8, David Gisselsson9, Norbert Graf10, Manfred Gessler2 and Kathy Pritchard-Jones1

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

Correspondence to:

Richard D. Williams, email:

Keywords: Wilms tumour, MYCN, copy number, DNA methylation, prognostic marker

Received: August 08, 2014 Accepted: January 14, 2015 Published: January 31, 2015

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.


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