gms | German Medical Science

60. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie (DGNN)

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie

26. - 28.08.2015, Berlin

DNA methylation array-based molecular profiling for brain tumor classification

Meeting Abstract

  • corresponding author presenting/speaker David Capper - University Heidelberg, Neuropathology, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), CCU Neuropathology, Heidelberg, Germany
  • David T. W. Jones - German Cancer Research Center (DKFZ), Division of Pediatric Neurooncology, Heidelberg, Germany
  • Martin Sill - German Cancer Research Center (DKFZ), Division of Biostatistics, Heidelberg, Germany
  • Volker Hovestadt - German Cancer Research Center (DKFZ), Division of Molecular Genetics, Heidelberg, Germany
  • Daniel Schrimpf - University Heidelberg, Neuropathology, Heidelberg, Germany
  • David Reuss - University Heidelberg, Neuropathology, Heidelberg, Germany
  • Felix Sahm - University Heidelberg, Neuropathology, Heidelberg, Germany
  • Christian Kölsche - University Heidelberg, Neuropathology, Heidelberg, Germany
  • Annekathrin Kratz - University Heidelberg, Neuropathology, Heidelberg, Germany
  • Michel Mittelbronn - Goethe University, Institute of Neurology (Edinger Institute), Frankfurt, Germany
  • Jens Schittenhelm - University Tübingen, Department of Neuropathology, Tübingen, Germany
  • Adriana Olar - MD Anderson Cancer Center, Department of Pathology, Houston, United States
  • Rolf Buslei - Friedrich-Alexander University Erlangen-Nürnberg, Department of Neuropathology, Erlangen, Germany
  • Christian Hartmann - Hannover Medical School, Department of Neuropathology, Hannover, Germany
  • Patricia Kohlhof - Stuttgart Hospital, Institute of Pathology, Stuttgart, Germany
  • Martin Hasselblatt - University Hospital Münster, Institute of Neuropathology, Münster, Germany
  • Matthias Schick - German Cancer Research Center (DKFZ), Genomics and Proteomics Core Facility, Heidelberg, Germany
  • Melanie Bewerunge-Hudler - German Cancer Research Center (DKFZ), Genomics and Proteomics Core Facility, Heidelberg, Germany
  • Andrey Korshunov - University Heidelberg, Neuropathology, Heidelberg, Germany
  • Kenneth Aldape - Princess Margaret Cancer Center, MacFeeters-Hamilton Brain Tumour Center, Toronto, Canada
  • Andreas von Deimling - University Heidelberg, Neuropathology, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), CCU Neuropathology, Heidelberg, Germany
  • Stefan M. Pfister - German Cancer Research Center (DKFZ), Division of Pediatric Neurooncology, Heidelberg, Germany; University Hospital Heidelberg, Department of Pediatric Oncology, Hematology and Immunology, Heidelberg, Germany

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. 60th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN). Berlin, 26.-28.08.2015. Düsseldorf: German Medical Science GMS Publishing House; 2015. Doc15dgnnNO4

doi: 10.3205/15dgnn12, urn:nbn:de:0183-15dgnn123

Veröffentlicht: 25. August 2015

© 2015 Capper et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Question/methods: Molecular technologies which can complement standard pathology testing have the potential to greatly enhance diagnostic precision. Analysis of DNA methylation, acting as a 'fingerprint' of cellular origin, is one such promising technology for tumor classification. We have established a brain tumor DNA methylation profile reference bank consisting of more than 2,000 cases using the Illumina HumanMethylation450 (450k) array, with over 70 brain tumor entities or subgroups represented. The array platform works from frozen or paraffin-embedded material, with minimal DNA input. A random forest algorithm has been established to compare diagnostic cases with the reference cohort resulting in an entity prediction with an associated probability score. Genome-wide copy number profiles and target gene methylation data (e.g. MGMT) generated from the array provide additional diagnostic information.

Results: We have analysed more than 1000 diagnostic samples from Heidelberg University Hospital and external institutions with this classification scheme. A considerable number of cases displayed a discrepancy between histological and molecular diagnoses. The rate of discrepancies varies between entities and interestingly also between age groups. For example the rate of discrepancies is relatively low for glioblastomas above the age of 30 years (n=183, discrepancy in 3%) but considerably higher in patients below 30 years (n=48, discrepancy in 24%). Careful re-examination of these cases often resulted in refinement of the original diagnosis, in several cases resulting in a change of suggested patient care. Furthermore, we have collected evidence of further subgroups of certain entities and associations with recurrent copy number changes. These subgroups await further characterization.

Conclusions: We present the establishment and feasibility of diagnostic implementation of a DNA methylation based brain tumor classification scheme. By the analysis of over 1000 prospective diagnostic cases we can demonstrate that the utility of this method varies from entity to entity or between age groups within specific entities. In our experience, for many cases DNA methylation profiling provides an assuring confirmation of histological diagnosis. For cases with discrepant results additional diagnostic workup and reconsideration of the histological diagnosis is highly advocated. We further demonstrate that for many unclear histological cases additional diagnostic information can be derived from methylation profiles.