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 - TY - JOUR A1 - Postema, Merel C. A1 - Hoogman, Martine A1 - Ambrosino, Sara A1 - Asherson, Philip A1 - Banaschewski, Tobias A1 - Bandeira, Cibele E. A1 - Baranov, Alexandr A1 - Bau, Claiton H.D. A1 - Baumeister, Sarah A1 - Baur‐Streubel, Ramona A1 - Bellgrove, Mark A. A1 - Biederman, Joseph A1 - Bralten, Janita A1 - Brandeis, Daniel A1 - Brem, Silvia A1 - Buitelaar, Jan K. A1 - Busatto, Geraldo F. A1 - Castellanos, Francisco X. A1 - Cercignani, Mara A1 - Chaim‐Avancini, Tiffany M. A1 - Chantiluke, Kaylita C. A1 - Christakou, Anastasia A1 - Coghill, David A1 - Conzelmann, Annette A1 - Cubillo, Ana I. A1 - Cupertino, Renata B. A1 - de Zeeuw, Patrick A1 - Doyle, Alysa E. A1 - Durston, Sarah A1 - Earl, Eric A. A1 - Epstein, Jeffery N. A1 - Ethofer, Thomas A1 - Fair, Damien A. A1 - Fallgatter, Andreas J. A1 - Faraone, Stephen V. A1 - Frodl, Thomas A1 - Gabel, Matt C. A1 - Gogberashvili, Tinatin A1 - Grevet, Eugenio H. A1 - Haavik, Jan A1 - Harrison, Neil A. A1 - Hartman, Catharina A. A1 - Heslenfeld, Dirk J. A1 - Hoekstra, Pieter J. A1 - Hohmann, Sarah A1 - Høvik, Marie F. A1 - Jernigan, Terry L. A1 - Kardatzki, Bernd A1 - Karkashadze, Georgii A1 - Kelly, Clare A1 - Kohls, Gregor A1 - Konrad, Kerstin A1 - Kuntsi, Jonna A1 - Lazaro, Luisa A1 - Lera‐Miguel, Sara A1 - Lesch, Klaus‐Peter A1 - Louza, Mario R. A1 - Lundervold, Astri J. A1 - Malpas, Charles B A1 - Mattos, Paulo A1 - McCarthy, Hazel A1 - Namazova‐Baranova, Leyla A1 - Nicolau, Rosa A1 - Nigg, Joel T. A1 - Novotny, Stephanie E. A1 - Oberwelland Weiss, Eileen A1 - O'Gorman Tuura, Ruth L. A1 - Oosterlaan, Jaap A1 - Oranje, Bob A1 - Paloyelis, Yannis A1 - Pauli, Paul A1 - Picon, Felipe A. A1 - Plessen, Kerstin J. A1 - Ramos‐Quiroga, J. Antoni A1 - Reif, Andreas A1 - Reneman, Liesbeth A1 - Rosa, Pedro G.P. A1 - Rubia, Katya A1 - Schrantee, Anouk A1 - Schweren, Lizanne J.S. A1 - Seitz, Jochen A1 - Shaw, Philip A1 - Silk, Tim J. A1 - Skokauskas, Norbert A1 - Soliva Vila, Juan C. A1 - Stevens, Michael C. A1 - Sudre, Gustavo A1 - Tamm, Leanne A1 - Tovar‐Moll, Fernanda A1 - van Erp, Theo G.M. A1 - Vance, Alasdair A1 - Vilarroya, Oscar A1 - Vives‐Gilabert, Yolanda A1 - von Polier, Georg G. A1 - Walitza, Susanne A1 - Yoncheva, Yuliya N. A1 - Zanetti, Marcus V. A1 - Ziegler, Georg C. A1 - Glahn, David C. A1 - Jahanshad, Neda A1 - Medland, Sarah E. A1 - Thompson, Paul M. A1 - Fisher, Simon E. A1 - Franke, Barbara A1 - Francks, Clyde T1 - Analysis of structural brain asymmetries in attention‐deficit/hyperactivity disorder in 39 datasets JF - Journal of Child Psychology and Psychiatry N2 - Objective Some studies have suggested alterations of structural brain asymmetry in attention‐deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left‐right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. Methods We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. Results There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from −0.18 to 0.18) and would not survive study‐wide correction for multiple testing. Conclusion Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait. KW - attention‐deficit KW - hyperactivity disorder KW - brain asymmetry KW - brain laterality KW - structural MRI KW - large‐scale data Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239968 VL - 62 IS - 10 SP - 1202 EP - 1219 ER - TY - JOUR A1 - Wegert, Jenny A1 - Vokuhl, Christian A1 - Collord, Grace A1 - Del Castillo Velasco-Herrera, Martin A1 - Farndon, Sarah J. A1 - Guzzo, Charlotte A1 - Jorgensen, Mette A1 - Anderson, John A1 - Slater, Olga A1 - Duncan, Catriona A1 - Bausenwein, Sabrina A1 - Streitenberger, Heike A1 - Ziegler, Barbara A1 - Furtwängler, Rhoikos A1 - Graf, Norbert A1 - Stratton, Michael R. A1 - Campbell, Peter J. A1 - Jones, David TW A1 - Koelsche, Christian A1 - Pfister, Stefan M. A1 - Mifsud, William A1 - Sebire, Neil A1 - Sparber-Sauer, Monika A1 - Koscielniak, Ewa A1 - Rosenwald, Andreas A1 - Gessler, Manfred A1 - Behjati, Sam T1 - Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants JF - Nature Communications N2 - Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors. KW - cancer KW - genetics Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233446 VL - 9 ER -