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DNA methylation-based reclassification of olfactory neuroblastoma

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A Correction to this article was published on 09 August 2018

This article has been updated

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.

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Change history

  • 09 August 2018

    In the original publication, the second name of the twentieth author was incorrect. It should read as ‘Miguel Sáinz-Jaspeado’. The original publication of the article has been updated to reflect the change. This correction was authored by Ulrich Schüller on behalf of all authors of the original publication.

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Acknowledgements

We are much obliged to the staff of the Center for Cancer Genome Discovery (CCGD) at the Dana-Farber Cancer Institute (Boston, US) for DNA sequencing and especially thank Paul van Hummelen and Aaron Thorner for assistance with interpretation of findings. We thank the Microarray unit of the Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ) for providing excellent DNA methylation services. We thank the DKFZ-Heidelberg Center for Personalized Oncology (DKFZ-HIPO) for technical support and funding through HIPO_036. In other parts, this work was supported by an Illumina Medical Research Grant. This work was further supported by the Deutsche Krebshilfe (Grant no. 111630) and the Fördergemeinschaft Kinderkrebs-Zentrum Hamburg e.V.

Author information

Author notes

  1. Rolf Buslei

    Present address: Institute of Pathology/Neuropathology, Klinikum am Bruderwald, Sozialstiftung Bamberg, Bamberg, Germany

  2. Julika Ribbat-Idel & Sven Perner

    Present address: Pathology, University Hospital Schleswig-Holstein, Campus Lübeck, 23538, Lübeck, Germany

  3. Julika Ribbat-Idel & Sven Perner

    Present address: Research Center Borstel, Leibniz Center for Medicine and Biosciences, 23845, Borstel, Germany

  4. David Capper, Nils W. Engel, and Damian Stichel contributed equally to this work.

Authors and Affiliations

  1. Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    David Capper, Damian Stichel, Christian Koelsche, Daniel Schrimpf, Annika K. Wefers & Andreas von Deimling

  2. Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany

    David Capper, Christian Koelsche, Daniel Schrimpf, Annika K. Wefers & Andreas von Deimling

  3. Center for Neuropathology, Ludwig-Maximilians-University, Munich, Germany

    Nils W. Engel & Ulrich Schüller

  4. 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

    Nils W. Engel

  5. Royal National Throat, Nose and Ear Hospital, University College London Hospitals NHS Trust, London, UK

    Matt Lechner & Valerie J. Lund

  6. UCL Cancer Institute, University College London, London, UK

    Matt Lechner & Martin Forster

  7. Head and Neck Centre, University College London Hospitals NHS Trust, London, UK

    Matt Lechner, Martin Forster & Valerie J. Lund

  8. Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany

    David T. W. Jones, Martin Sill & Stefan Pfister

  9. Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    David T. W. Jones, Martin Sill & Stefan Pfister

  10. Department of Internal Medicine III, University Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany

    Oliver Weigert

  11. Department of Medical Oncology and Center for Molecular Oncologic Pathology, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, MA, USA

    Keith L. Ligon

  12. Departments of Pathology and Laboratory Medicine and Neurosurgery, Medical University of South Carolina and Hollings Cancer Center, Charleston, SC, USA

    Adriana Olar

  13. Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany

    David Capper, Stefanie Glöss, Simone Schmid & Arend Koch

  14. Institute of Neuropathology, Berlin Institute of Health, Berlin, Germany

    David Capper, Stefanie Glöss & Simone Schmid

  15. German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany

    David Capper, Stefanie Glöss & Simone Schmid

  16. Institute of Neuropathology, University Hospital Münster, Münster, Germany

    Werner Paulus

  17. Medical Faculty, Institute of Neuropathology, Heinrich Heine University, Düsseldorf, Germany

    Jörg Felsberg & Guido Reifenberger

  18. German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Düsseldorf, Germany

    Jörg Felsberg & Guido Reifenberger

  19. Institute of Neuropathology, University Medical Center Hamburg, Hamburg, Germany

    Markus Glatzel & Ulrich Schüller

  20. Department of Pathology, Universitätsspital Basel, Basel, Switzerland

    Stephan Frank

  21. Institute of Pathology, Julius-Maximilians-University, Würzburg, Germany

    Camelia M. Monoranu

  22. Department of Neuropathology, University of Erlangen, Erlangen, Germany

    Rolf Buslei

  23. Institute of Pathology, University Hospital Bonn, Bonn, Germany

    Julika Ribbat-Idel & Sven Perner

  24. ENT Department, Universitätsklinikum Carl Gustav Carus Dresden, Dresden, Germany

    Volker Gudziol

  25. Institute for Pathology, Universitätsklinikum Carl Gustav Carus Dresden, Dresden, Germany

    Matthias Meinhardt

  26. Department of Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf, Germany

    Judith Niesen & Ulrich Schüller

  27. Research Institute Children’s Cancer Center Hamburg, Hamburg, Germany

    Judith Niesen & Ulrich Schüller

  28. Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany

    Stefan Pfister

  29. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain

    Sebastian Moran & Manel Esteller

  30. Sarcoma Research Group, Molecular Oncology Lab, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain

    Oscar M. Tirado & Miguel Sáinz-Jaspeado

  31. Department of Pediatric Onco-Hematology and Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Barcelona, Catalonia, Spain

    Jaume Mora

  32. Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain

    Manel Esteller

  33. Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain

    Manel Esteller

  34. Pediatric Solid Tumor Laboratory, Human Genetic Department, Research Institute of Rare Diseases, Instituto de Salud Carlos III, Madrid, Spain

    Javier Alonso

  35. Oncology Department, ICO-IDIBELL, Barcelona, Spain

    Xavier Garcia del Muro

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Corresponding author

Correspondence to Ulrich Schüller.

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Conflict of interest

Andreas von Deimling, David Jones, and David Capper share inventorship of a “DNA-methylation-based method for classifying tumor species of the brain”. A patent has been applied for this method (EP 3067432 A1). All terms are being managed by the German Cancer Research Center in accordance with its conflict of interest policies. G. Reifenberger has received research grants from Roche and Merck Serono, and honoraria for lectures or advisory boards from Amgen and Celldex. The other authors declare no conflicts of interest.

Additional information

The original version of this article has been updated: the second name of the twentieth author was incorrect. It should read as ‘Miguel Sáinz-Jaspeado’.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Figure

 1. Analysis of possible sub-clusters within “Core ONB”. A. Unsupervised hierarchical cluster analysis of DNA methylation data from “Core ONB” group samples (n = 42) of the initial methylation cluster analysis revealed further subdivision of the “Core ONB” DNA methylation group into two putative clusters: “Core ONB A” (n = 24) and “Core ONB B” (n = 18). B. The methylation subgroups “Core ONB A” and “Core ONB B” were compared on the level of histomorphology (H&E staining; B-C) and for expression patterns of selected immunohistochemical markers S100 (E–F), chromogranin A (H-I) and cytokeratin (K-L). The images illustrate representative staining results for each marker in both groups. Scale bar is 100 µm (only visualized in B). Bar graphs display comparisons of distributions of values for variables “Hyams grade” (D) as well as “S100” (G), “chromogranin A” (J) and “cytokeratin” (M) between tumor groups. The distributions of staining patterns between “Core ONB A” and “Core ONB B” tumors did not differ significantly for any variable tested (D, G, J and M). (PDF 1587 kb)

Supplementary Figure

 2. Comparative copy number variation (CNV) profiling of DNA methylation subgroups “Core ONB A” and “Core ONB B”. A. CNV profiles of the n = 42 “Core ONB” tumor samples are displayed according to the clustering order of Supplementary Figure 1 with highlighted subdivision into putative methylation subgroups “Core ONB A” (n = 24) and “Core ONB B” (n = 18). B. The comparison of cumulated CNV profiles between “Core ONB A” and “Core ONB B” showed identical complex cytogenetic aberrations with recurrent losses of chromosomes 1, 2, 3, 4, 8, 9, 10, and 12 in both groups, further justifying their merge to an “Core ONB” DNA methylation group. (PDF 492 kb)

Supplementary Figure

 3. Assessment of overall CpG methylation and CpG island methylation levels. A. The distribution of mean beta-values for all CpG probes of the methylation array was displayed as box plots for the sinonasal tumor groups “Core ONB”, Sinonasal IDH2 carcinoma”, “Sinonasal tumors, high meth.”, Other sinonasal tumors” and two additional brain tumor groups with established CIMP status (IDH-mutated astrocytoma and oligodendroglioma) to allow for comparison of “overall CpG methylation” between tumor groups. “Sinonasal IDH2 carcinoma” and “Sinonasal tumors, high meth.” demonstrated relatively high overall CpG methylation. B. The same analysis for CpG probes of the methylation array mapped to CpG islands revealed similar high levels of CpG island methylation between CIMP reference brain tumor groups and “Sinonasal IDH2 carcinoma”, prompting the assumption of CIMP status for this group in accordance with detected recurrent IDH2 mutations. C. Density plot analysis of the distribution of beta-values (“methylation ratio”) of all probes mapped to CpG islands for individual tumor samples confirmed relative hypermethylation of CpG islands for tumor samples of the “Sinonasal IDH2 carcinoma” methylation group in comparison to “Core ONB” and “Other sinonasal tumors”. An individual case from the “Sinonasal tumors, high methylation” group showed similar pronounced CpG island methylation, but no IDH1/2-mutation. (PDF 439 kb)

Supplementary Figure

 4. Baseline characteristics and survival analysis of tumor groups. A. Baseline characteristics of tumor groups: The clinical attributes “Median age” and “Sex” were operationalized and compared by Kruskal–Wallis and Dunn’s post testing for “Median age” and by Chi-square testing for “Sex” between tumor groups. “Median age” was significantly different between “Core ONB” and “Sinonasal tumors, high methylation”. B. Kaplan–Meier survival analysis for tumor groups: A meaningful calculation of overall survival (OS) and group comparison was not possible due to limited clinical follow-up data. (PDF 134 kb)

Supplementary Table

 1. Overview of the institutionally diagnosed (histopathologically defined) olfactory neuroblastoma cohort. (XLSX 13 kb)

Supplementary Table

 2. List of genes included in the OncoPanel version 3 exome sequencing panel. (XLSX 22 kb)

Supplementary Table

 3. List of likely somatic non-synonymous variants with possible pathogenic and biological impact in “Core ONB” and “Sinonasal tumors with IDH2 mutation”. (XLSX 12 kb)

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Capper, D., Engel, N.W., Stichel, D. et al. DNA methylation-based reclassification of olfactory neuroblastoma. Acta Neuropathol 136, 255–271 (2018). https://doi.org/10.1007/s00401-018-1854-7

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