Article ; Online: Multiple mechanisms of MYCN dysregulation in Wilms tumour.
2015 Volume 6, Issue 9, Page(s) 7232–7243
Abstract: ... in several childhood cancers. Here we present a comprehensive copy number analysis of MYCN in Wilms tumour (WT ... of Wilms tumour. We conclude that MYCN gain is prognostically significant, and suggest that the novel P44L ... aberration. Our results suggest a significant role for MYCN dysregulation in the molecular biology ...
| 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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| MeSH term(s) | DNA Methylation ; DNA Mutational Analysis ; Disease-Free Survival ; Exome ; Gene Dosage ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genes, myc ; Genes, p53 ; Humans ; Kaplan-Meier Estimate ; Kidney Neoplasms/genetics ; Kidney Neoplasms/metabolism ; Mutation ; Neoplasm Recurrence, Local/genetics ; Oligonucleotide Array Sequence Analysis ; Point Mutation ; Polymorphism, Single Nucleotide ; Prognosis ; Proto-Oncogene Mas ; Proto-Oncogene Proteins c-myc/metabolism ; Tumor Suppressor Protein p53/metabolism ; Wilms Tumor/genetics ; Wilms Tumor/metabolism |
| Chemical Substances | MAS1 protein, human ; Proto-Oncogene Mas ; Proto-Oncogene Proteins c-myc ; TP53 protein, human ; Tumor Suppressor Protein p53 |
| Language | English |
| Publishing date | 2015-03-07 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2560162-3 |
| ISSN | 1949-2553 ; 1949-2553 |
| ISSN (online) | 1949-2553 |
| ISSN | 1949-2553 |
| DOI | 10.18632/oncotarget.3377 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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