Multiple mechanisms of MYCN dysregulation in Wilms tumour.
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.
UCL Institute of Child Health, London, UK.
Richard D
RD
Williams
UCL Institute of Child Health, London, UK.
Tasnim
T
Chagtai
UCL Institute of Child Health, London, UK.
Marisa
M
Alcaide-German
UCL Institute of Child Health, London, UK.
John
J
Apps
Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry and Comprehensive Cancer Center Mainfranken, Wuerzburg University, Wuerzburg, Germany.
Jenny
J
Wegert
Institute of Cancer Research, Sutton, Surrey, UK.
Sergey
S
Popov
Cardiff University School of Medicine, Heath Park, Cardiff, UK.
Gordan
G
Vujanic
Biometrics Department, Netherlands Cancer Institute, Antonie van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands.
Harm
H
van Tinteren
Department of Pediatric Oncology/Hematology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands.
Marry M
MM
van den Heuvel-Eibrink
German Cancer Research Centre, Heidelberg, Germany.
Marcel
M
Kool
Academic Medical Center, Amsterdam, The Netherlands.
Jan
J
de Kraker
Department of Clinical Genetics, Lund University, Sweden.
David
D
Gisselsson
Department of Paediatric Oncology and Haematology, Saarland University Hospital, Homburg/Saar, Germany.
Norbert
N
Graf
Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry and Comprehensive Cancer Center Mainfranken, Wuerzburg University, Wuerzburg, Germany.
Manfred
M
Gessler
UCL Institute of Child Health, London, UK.
Kathy
K
Pritchard-Jones
D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D059472:Exome; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D016158:Genes, p53; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D009396:Wilms Tumor / Q000235:genetics / Q000378:metabolism*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
DNA methylation; MYCN; Wilms tumour; copy number; prognostic marker