@article{WelterWagnerFurtwaengleretal.2021, author = {Welter, Nils and Wagner, Angelo and Furtw{\"a}ngler, Rhoikos and Melchior, Patrick and Kager, Leo and Vokuhl, Christian and Schenk, Jens-Peter and Meier, Clemens Magnus and Siemer, Stefan and Gessler, Manfred and Graf, Norbert}, title = {Characteristics of nephroblastoma/nephroblastomatosis in children with a clinically reported underlying malformation or cancer predisposition syndrome}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {19}, issn = {2072-6694}, doi = {10.3390/cancers13195016}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248434}, year = {2021}, abstract = {(1) Background: about 10\% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. (2) Methods: this retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. (3) Results: Genitourinary malformations (GU, N = 66, 2.3\%), Beckwith-Wiedemann spectrum (BWS, N = 32, 1.1\%), isolated hemihypertrophy (IHH, N = 29, 1.0\%), Denys-Drash syndrome (DDS, N = 24, 0.8\%) and WAGR syndrome (N = 20, 0.7\%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24.5 months vs. 39.0 months), had smaller tumors (349.4 mL vs. 487.5 mL), less often metastasis (8.2\% vs. 18\%), but more often nephroblastomatosis (12.9\% vs. 1.9\%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30\%), DDS (29\%) and BWS (31\%). Chemotherapy induced reduction in tumor volume was poor in DDS (0.4\% increase) and favorable in BWS (86.9\% reduction). The event-free survival (EFS) of patients with BWS was significantly (p = 0.002) worse than in others. (4) Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.}, language = {en} } @article{WelterWagnerFurtwaengleretal.2021, author = {Welter, Nils and Wagner, Angelo and Furtw{\"a}ngler, Rhoikos and Melchior, Patrick and Kager, Leo and Vokuhl, Christian and Schenk, Jens-Peter and Meier, Clemens Magnus and Siemer, Stefan and Gessler, Manfred and Graf, Norbert}, title = {Correction: Welter et al. Characteristics of nephroblastoma/nephroblastomatosis in children with a clinically reported underlying malformation or cancer predisposition syndrome. Cancers 2021, 13, 5016}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {22}, issn = {2072-6694}, doi = {10.3390/cancers13225743}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250135}, year = {2021}, abstract = {In the original article [1] there was a mistake in Table 2 as published. Table 2 contains wrong percentages in lines Bilateral disease and Patients with CPS or GU. For this reason the table should be replaced with the correct one as shown below.}, language = {en} } @article{MartinSchlosserFurtwaengleretal.2021, author = {Mart{\´i}n, Ovidio Jim{\´e}nez and Schlosser, Andreas and Furtw{\"a}ngler, Rhoikos and Wegert, Jenny and Gessler, Manfred}, title = {MYCN and MAX alterations in Wilms tumor and identification of novel N-MYC interaction partners as biomarker candidates}, series = {Cancer Cell International}, volume = {21}, journal = {Cancer Cell International}, doi = {10.1186/s12935-021-02259-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265542}, year = {2021}, abstract = {Background Wilms tumor (WT) is the most common renal tumor in childhood. Among others, MYCN copy number gain and MYCN P44L and MAX R60Q mutations have been identified in WT. MYCN encodes a transcription factor that requires dimerization with MAX to activate transcription of numerous target genes. MYCN gain has been associated with adverse prognosis in different childhood tumors including WT. The MYCN P44L and MAX R60Q mutations, located in either the transactivating or basic helix-loop-helix domain, respectively, are predicted to be damaging by different pathogenicity prediction tools, but the functional consequences remain to be characterized. Methods We screened a large cohort of unselected WTs for MYCN and MAX alterations. Wild-type and mutant protein function were characterized biochemically, and we analyzed the N-MYC protein interactome by mass spectrometric analysis of N-MYC containing protein complexes. Results Mutation screening revealed mutation frequencies of 3\% for MYCN P44L and 0.9\% for MAX R60Q that are associated with a higher risk of relapse. Biochemical characterization identified a reduced transcriptional activation potential for MAX R60Q, while the MYCN P44L mutation did not change activation potential or protein stability. The protein interactome of N-MYC-P44L was likewise not altered as shown by mass spectrometric analyses of purified N-MYC complexes. Nevertheless, we could identify a number of novel N-MYC partner proteins, e.g. PEG10, YEATS2, FOXK1, CBLL1 and MCRS1, whose expression is correlated with MYCN in WT samples and several of these are known for their own oncogenic potential. Conclusions The strongly elevated risk of relapse associated with mutant MYCN and MAX or elevated MYCN expression corroborates their role in WT oncogenesis. Together with the newly identified co-expressed interactors they expand the range of potential biomarkers for WT stratification and targeting, especially for high-risk WT.}, language = {en} } @article{WegertVokuhZiegleretal.2017, author = {Wegert, Jenny and Vokuh, Christian and Ziegler, Barbara and Ernestus, Karen and Leuschner, Ivo and Furtw{\"a}ngler, Rhoikos and Graf, Norbert and Gessler, Manfred}, title = {TP53 alterations in Wilms tumour represent progression events with strong intratumour heterogeneity that are closely linked but not limited to anaplasia}, series = {The Journal of Pathology: Clinical Research}, volume = {3}, journal = {The Journal of Pathology: Clinical Research}, doi = {10.1002/cjp2.77}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158302}, pages = {234-248}, year = {2017}, abstract = {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.}, language = {en} }