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Multiple mechanisms of MYCN dysregulation in Wilms tumour

Please always quote using this URN: urn:nbn:de:bvb:20-opus-143471
  • 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,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.show moreshow less

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Metadaten
Author: 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, Kathy Pritchard-Jones
URN:urn:nbn:de:bvb:20-opus-143471
Document Type:Journal article
Faculties:Medizinische Fakultät / Theodor-Boveri-Institut für Biowissenschaften
Language:English
Parent Title (English):Oncotarget
Year of Completion:2015
Volume:6
Issue:9
Pagenumber:7232-7243
Source:Oncotarget, Vol. 6, No. 9, 7232-7243 (2015). DOI: 10.18632/oncotarget.3377
DOI:https://doi.org/10.18632/oncotarget.3377
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:DNA methylation; MYCN; Wilms tumour; beta-catenin; copy number; gain; gene; histology; integrative genomics viewer; oncogene amplification; prognostic marker; reveals; sequencing data; somatic mutations
Release Date:2018/05/22
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung