TY  - JOUR
A1  - Williams, Richard D.
A1  - Chagtai, Tasnim
A1  - Alcaide-German, Marisa
A1  - Apps, John
A1  - Wegert, Jenny
A1  - Popov, Sergey
A1  - Vujanic, Gordan
A1  - Van Tinteren, Harm
A1  - Van den Heuvel-Eibrink, Marry M
A1  - Kool, Marcel
A1  - De Kraker, Jan
A1  - Gisselsson, David
A1  - Graf, Norbert
A1  - Gessler, Manfred
A1  - Pritchard-Jones, Kathy
T1  - Multiple mechanisms of MYCN dysregulation in Wilms tumour
JF  - Oncotarget
N2  - 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.
KW  - integrative genomics viewer
KW  - oncogene amplification
KW  - sequencing data
KW  - gene
KW  - gain
KW  - copy number
KW  - somatic mutations
KW  - beta-catenin
KW  - histology
KW  - reveals
KW  - Wilms tumour
KW  - MYCN
KW  - DNA methylation
KW  - prognostic marker
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143471
VL  - 6
IS  - 9
ER  - 
TY  - JOUR
A1  - Wegert, Jenny
A1  - Vokuh, Christian
A1  - Ziegler, Barbara
A1  - Ernestus, Karen
A1  - Leuschner, Ivo
A1  - Furtwängler, Rhoikos
A1  - Graf, Norbert
A1  - Gessler, Manfred
T1  - TP53 alterations in Wilms tumour represent progression events with strong intratumour heterogeneity that are closely linked but not limited to anaplasia
JF  - The Journal of Pathology: Clinical Research
N2  - TP53 mutations have been associated with anaplasia in Wilms tumour, which conveys a high risk for relapse and fatal outcome. Nevertheless, TP53 alterations have been reported in no more than 60% of anaplastic tumours, and recent data have suggested their presence in tumours that do not fulfil the criteria for anaplasia, questioning the clinical utility of TP53 analysis. Therefore, we characterized the TP53 status in 84 fatal cases of Wilms tumour, irrespective of histological subtype. We identified TP53 alterations in at least 90% of fatal cases of anaplastic Wilms tumour, and even more when diffuse anaplasia was present, indicating a very strong if not absolute coupling between anaplasia and deregulation of p53 function. Unfortunately, TP53 mutations do not provide additional predictive value in anaplastic tumours since the same mutation rate was found in a cohort of non-fatal anaplastic tumours. When classified according to tumour stage, patients with stage I diffuse anaplastic tumours still had a high chance of survival (87%), but this rate dropped to 26% for stages II–IV. Thus, volume of anaplasia or possible spread may turn out to be critical parameters. Importantly, among non-anaplastic fatal tumours, 26% had TP53 alterations, indicating that TP53 screening may identify additional cases at risk. Several of these non-anaplastic tumours fulfilled some criteria for anaplasia, for example nuclear unrest, suggesting that such partial phenotypes should be under special scrutiny to enhance detection of high-risk tumours via TP53 screening. A major drawback is that these alterations are secondary changes that occur only later in tumour development, leading to striking intratumour heterogeneity that requires multiple biopsies and analysis guided by histological criteria. In conclusion, we found a very close correlation between histological signs of anaplasia and TP53 alterations. The latter may precede development of anaplasia and thereby provide diagnostic value pointing towards aggressive disease.
KW  - tumour heterogeneity
KW  - Wilms tumour
KW  - nephroblastoma
KW  - anaplasia
KW  - TP53
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158302
VL  - 3
ER  -