DNA methylation-based reclassification of olfactory neuroblastoma View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-05-05

AUTHORS

David Capper, Nils W. Engel, Damian Stichel, Matt Lechner, Stefanie Glöss, Simone Schmid, Christian Koelsche, Daniel Schrimpf, Judith Niesen, Annika K. Wefers, David T. W. Jones, Martin Sill, Oliver Weigert, Keith L. Ligon, Adriana Olar, Arend Koch, Martin Forster, Sebastian Moran, Oscar M. Tirado, Miguel Sáinz-Jaspeado, Jaume Mora, Manel Esteller, Javier Alonso, Xavier Garcia del Muro, Werner Paulus, Jörg Felsberg, Guido Reifenberger, Markus Glatzel, Stephan Frank, Camelia M. Monoranu, Valerie J. Lund, Andreas von Deimling, Stefan Pfister, Rolf Buslei, Julika Ribbat-Idel, Sven Perner, Volker Gudziol, Matthias Meinhardt, Ulrich Schüller

ABSTRACT

Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes. DNA methylation profiles were compared to those of relevant differential diagnoses of ONB. Unsupervised hierarchical clustering analysis of DNA methylation data revealed four subgroups among institutionally diagnosed ONB. The largest group (n = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis. A second DNA methylation group (n = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases. T-SNE analysis clustered these cases together with sinonasal carcinoma with IDH2 mutation. Four cases (6%) formed a small group characterized by an overall high level of DNA methylation, but without CIMP. The fourth group consisted of 13 cases that had heterogeneous DNA methylation profiles and strong cytokeratin expression in most cases. In t-SNE analysis, these cases mostly grouped among sinonasal adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma. Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1–4, 8–10, and 12. NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A. In conclusion, we demonstrate that institutionally diagnosed ONB are a heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the mutational status of IDH2 as well as DNA methylation patterns may greatly aid in the precise classification of ONB. More... »

PAGES

255-271

References to SciGraph publications

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  • Journal

    TITLE

    Acta Neuropathologica

    ISSUE

    2

    VOLUME

    136

    Author Affiliations

  • German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany
  • Department of Oncology and Hematology with Sections Bone Marrow Transplant and Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg, Hamburg, Germany
  • Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
  • Head and Neck Centre, University College London Hospitals NHS Trust, London, UK
  • Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany
  • Research Institute Children’s Cancer Center Hamburg, Hamburg, Germany
  • Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
  • Department of Internal Medicine III, University Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany
  • Department of Medical Oncology and Center for Molecular Oncologic Pathology, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, MA, USA
  • Departments of Pathology and Laboratory Medicine and Neurosurgery, Medical University of South Carolina and Hollings Cancer Center, Charleston, SC, USA
  • Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
  • Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain
  • Sarcoma Research Group, Molecular Oncology Lab, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain
  • Department of Pediatric Onco-Hematology and Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Barcelona, Catalonia, Spain
  • Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
  • Pediatric Solid Tumor Laboratory, Human Genetic Department, Research Institute of Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain
  • Oncology Department, ICO-IDIBELL, Barcelona, Spain
  • Institute of Neuropathology, University Hospital Münster, Münster, Germany
  • German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Düsseldorf, Germany
  • Institute of Neuropathology, University Medical Center Hamburg, Hamburg, Germany
  • Department of Pathology, Universitätsspital Basel, Basel, Switzerland
  • Institute of Pathology, Julius-Maximilians-University, Würzburg, Germany
  • Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany
  • Institute of Pathology/Neuropathology, Klinikum am Bruderwald, Sozialstiftung Bamberg, Bamberg, Germany
  • Research Center Borstel, Leibniz Center for Medicine and Biosciences, 23845, Borstel, Germany
  • ENT Department, Universitätsklinikum Carl Gustav Carus Dresden, Dresden, Germany
  • Institute for Pathology, Universitätsklinikum Carl Gustav Carus Dresden, Dresden, Germany
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s00401-018-1854-7

    DOI

    http://dx.doi.org/10.1007/s00401-018-1854-7

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1103827875

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29730775


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