Metabolomics, machine learning and immunohistochemistry to predict succinate dehydrogenase mutational status in phaeochromocytomas and paragangliomas.

Journal: The Journal of pathology
PMID: 32462735

Abstract

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours with a hereditary background in over one-third of patients. Mutations in succinate dehydrogenase (SDH) genes increase the risk for PPGLs and several other tumours. Mutations in subunit B (SDHB) in particular are a risk factor for metastatic disease, further highlighting the importance of identifying SDHx mutations for patient management. Genetic variants of unknown significance, where implications for the patient and family members are unclear, are a problem for interpretation. For such cases, reliable methods for evaluating protein functionality are required. Immunohistochemistry for SDHB (SDHB-IHC) is the method of choice but does not assess functionality at the enzymatic level. Liquid chromatography-mass spectrometry-based measurements of metabolite precursors and products of enzymatic reactions provide an alternative method. Here, we compare SDHB-IHC with metabolite profiling in 189 tumours from 187 PPGL patients. Besides evaluating succinate:fumarate ratios (SFRs), machine learning algorithms were developed to establish predictive models for interpreting metabolite data. Metabolite profiling showed higher diagnostic specificity compared to SDHB-IHC (99.2% versus 92.5%, p = 0.021), whereas sensitivity was comparable. Application of machine learning algorithms to metabolite profiles improved predictive ability over that of the SFR, in particular for hard-to-interpret cases of head and neck paragangliomas (AUC 0.9821 versus 0.9613, p = 0.044). Importantly, the combination of metabolite profiling with SDHB-IHC has complementary utility, as SDHB-IHC correctly classified all but one of the false negatives from metabolite profiling strategies, while metabolite profiling correctly classified all but one of the false negatives/positives from SDHB-IHC. From 186 tumours with confirmed status of SDHx variant pathogenicity, the combination of the two methods resulted in 185 correct predictions, highlighting the benefits of both strategies for patient management. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Authors

  • Paal W Wallace
    Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • Catleen Conrad
    Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • Sascha Brückmann
    Institute of Pathology, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • Ying Pang
    Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Eduardo Caleiras
    Histopathology Core Unit, Spanish National Cancer Research Centre (CNIO), Calle de Melchor Fernández Almagro, Madrid, Spain.
  • Masanori Murakami
    Division of Vascular Surgery, Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
  • Esther Korpershoek
    Department of Pathology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
  • Zhengping Zhuang
    Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Elena Rapizzi
    Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
  • Matthias Kroiss
    Department of Internal Medicine, Division of Endocrinology, University Hospital, University of Würzburg, Würzburg, Germany.
  • Volker Gudziol
    Klinik für Hals-Nasen-Ohrenheilkunde, Kopf- und Hals-Chirurgie, Plastische Operationen, Städtisches Klinikum Dresden, Akademisches Lehrkrankenhaus der Technischen Universität Dresden, Dresden, Germany.
  • Henri Jlm Timmers
    Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
  • Massimo Mannelli
    Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
  • Jens Pietzsch
    Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
  • Felix Beuschlein
    Medizinische Klinik and Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany.
  • Karel Pacak
    Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
  • Mercedes Robledo
    Hereditary Endocrine Cancer Group, CNIO, Madrid, Spain and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
  • Barbara Klink
    Institute for Clinical Genetics, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • Mirko Peitzsch
    Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • Anthony J Gill
    Royal North Shore Hospital, Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Sydney, Australia.
  • Arthur S Tischler
    Department of Pathology and Laboratory Medicine, Tufts University School of Medicine, Boston, MA, USA.
  • Ronald R de Krijger
    Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
  • Thomas Papathomas
    Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, UK.
  • Daniela Aust
    Institute of Pathology, Tumor and Normal Tissue Bank of the UCC/NCT Dresden, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • Graeme Eisenhofer
    Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
  • Susan Richter
    Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

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