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Cancers (Basel). 2019 Jun 11;11(6). pii: E809. doi: 10.3390/cancers11060809.

Optimizing Genetic Workup in Pheochromocytoma and Paraganglioma by Integrating Diagnostic and Research Approaches.

Gieldon L1,2,3,4, William D5,6,7, Hackmann K8,9,10,11, Jahn W12,13,14, Jahn A15,16,17,18, Wagner J19,20,21,22, Rump A23,24,25,26, Bechmann N27, Nölting S28, Knösel T29, Gudziol V30, Constantinescu G31, Masjkur J32, Beuschlein F33, Timmers HJ34, Canu L35, Pacak K36, Robledo M37, Aust D38, Schröck E39,40,41,42, Eisenhofer G43,44, Richter S45, Klink B46,47,48,49,50.

Author information

1
Institute for Clinical Genetics, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany. Laura.Gieldon@tu-dresden.de.
2
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), 01307 Dresden, Germany. Laura.Gieldon@tu-dresden.de.
3
German Cancer Consortium (DKTK), 01307 Dresden, Germany. Laura.Gieldon@tu-dresden.de.
4
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Laura.Gieldon@tu-dresden.de.
5
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), 01307 Dresden, Germany. doreen.william@nct-dresden.de.
6
German Cancer Consortium (DKTK), 01307 Dresden, Germany. doreen.william@nct-dresden.de.
7
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. doreen.william@nct-dresden.de.
8
Institute for Clinical Genetics, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany. Karl.Hackmann@uniklinikum-dresden.de.
9
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), 01307 Dresden, Germany. Karl.Hackmann@uniklinikum-dresden.de.
10
German Cancer Consortium (DKTK), 01307 Dresden, Germany. Karl.Hackmann@uniklinikum-dresden.de.
11
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Karl.Hackmann@uniklinikum-dresden.de.
12
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), 01307 Dresden, Germany. w.jahn@dkfz-heidelberg.de.
13
German Cancer Consortium (DKTK), 01307 Dresden, Germany. w.jahn@dkfz-heidelberg.de.
14
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. w.jahn@dkfz-heidelberg.de.
15
Institute for Clinical Genetics, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany. Arne.Jahn@uniklinikum-dresden.de.
16
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), 01307 Dresden, Germany. Arne.Jahn@uniklinikum-dresden.de.
17
German Cancer Consortium (DKTK), 01307 Dresden, Germany. Arne.Jahn@uniklinikum-dresden.de.
18
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Arne.Jahn@uniklinikum-dresden.de.
19
Institute for Clinical Genetics, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany. Johannes.Wagner@uniklinikum-dresden.de.
20
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), 01307 Dresden, Germany. Johannes.Wagner@uniklinikum-dresden.de.
21
German Cancer Consortium (DKTK), 01307 Dresden, Germany. Johannes.Wagner@uniklinikum-dresden.de.
22
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Johannes.Wagner@uniklinikum-dresden.de.
23
Institute for Clinical Genetics, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany. Andreas.Rump@uniklinikum-dresden.de.
24
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), 01307 Dresden, Germany. Andreas.Rump@uniklinikum-dresden.de.
25
German Cancer Consortium (DKTK), 01307 Dresden, Germany. Andreas.Rump@uniklinikum-dresden.de.
26
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Andreas.Rump@uniklinikum-dresden.de.
27
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany. Nicole.Bechmann@uniklinikum-dresden.de.
28
Medizinische Klinik und Poliklinik IV, Klinikum der Universität, LMU München, 80336 Munich, Germany. Svenja.Noelting@med.uni-muenchen.de.
29
Institute of Pathology, Ludwig-Maximilians-University, 80337 Munich, Germany. Thomas.Knoesel@med.uni-muenchen.de.
30
Department of Otorhinolaryngology Head and Neck Surgery, Municipal Hospital Dresden, 01067 Dresden, Germany. Volker.Gudziol@uniklinikum-dresden.de.
31
Department of Internal Medicine III, University Hospital Carl Gustav Carus at Technische Universität Dresden, 01307 Dresden, Germany. Georgiana.Constantinescu@uniklinikum-dresden.de.
32
Department of Internal Medicine III, University Hospital Carl Gustav Carus at Technische Universität Dresden, 01307 Dresden, Germany. Jimmy.Masjkur@med.uni-heidelberg.de.
33
Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, 8091 Zürich, Switzerland. felix.beuschlein@usz.ch.
34
Department of Internal Medicine, Radboud University Medical Centre, 6525 Nijmegen, The Netherlands. henri.timmers@radboudumc.nl.
35
Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50149 Florence, Italy. letizia.canu@unifi.it.
36
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. karel@mail.nih.gov.
37
Hereditary Endocrine Cancer Group, CNIO, Madrid, Spain and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain. mrobledo@cnio.es.
38
Institute of Pathology, Tumor and Normal Tissue Bank of the UCC/NCT Dresden, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany. Daniela.Aust@uniklinikum-dresden.de.
39
Institute for Clinical Genetics, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany. Evelin.Schroeck@uniklinikum-dresden.de.
40
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), 01307 Dresden, Germany. Evelin.Schroeck@uniklinikum-dresden.de.
41
German Cancer Consortium (DKTK), 01307 Dresden, Germany. Evelin.Schroeck@uniklinikum-dresden.de.
42
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Evelin.Schroeck@uniklinikum-dresden.de.
43
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany. Graeme.Eisenhofer@uniklinikum-dresden.de.
44
Department of Internal Medicine III, University Hospital Carl Gustav Carus at Technische Universität Dresden, 01307 Dresden, Germany. Graeme.Eisenhofer@uniklinikum-dresden.de.
45
Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany. Susan.Richter@uniklinikum-dresden.de.
46
Institute for Clinical Genetics, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany. Barbara.Klink@lns.etat.lu.
47
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), 01307 Dresden, Germany. Barbara.Klink@lns.etat.lu.
48
German Cancer Consortium (DKTK), 01307 Dresden, Germany. Barbara.Klink@lns.etat.lu.
49
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Barbara.Klink@lns.etat.lu.
50
National Center for Genetics (NCG), Laboratoire national de santé (LNS), 1, rue Louis Rech, 3555 Dudelange, Luxembourg. Barbara.Klink@lns.etat.lu.

Abstract

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors with a strong hereditary background and a large genetic heterogeneity. Identification of the underlying genetic cause is crucial for the management of patients and their families as it aids differentiation between hereditary and sporadic cases. To improve diagnostics and clinical management we tailored an enrichment based comprehensive multi-gene next generation sequencing panel applicable to both analyses of tumor tissue and blood samples. We applied this panel to tumor samples and compared its performance to our current routine diagnostic approach. Routine diagnostic sequencing of 11 PPGL susceptibility genes was applied to blood samples of 65 unselected PPGL patients at a single center in Dresden, Germany. Predisposing germline mutations were identified in 19 (29.2%) patients. Analyses of 28 PPGL tumor tissues using the dedicated PPGL panel revealed pathogenic or likely pathogenic variants in known PPGL susceptibility genes in 21 (75%) cases, including mutations in IDH2, ATRX and HRAS. These mutations suggest sporadic tumor development. Our results imply a diagnostic benefit from extended molecular tumor testing of PPGLs and consequent improvement of patient management. The approach is promising for determination of prognostic biomarkers that support therapeutic decision-making.

KEYWORDS:

CNV detection; hereditary; next-generation sequencing; paraganglioma; pheochromocytoma; sporadic

PMID:
31212687
DOI:
10.3390/cancers11060809
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