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Department of Clinical and Experimental Medicine, Department of Oncology-Pathology, Department of Surgery, Department of Clinical Science, Department of Molecular Medicine and Surgery, Department of Surgery, Faculty of Health Sciences, Linköping University, Linköping SE-58185, Sweden
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Department of Clinical and Experimental Medicine, Department of Oncology-Pathology, Department of Surgery, Department of Clinical Science, Department of Molecular Medicine and Surgery, Department of Surgery, Faculty of Health Sciences, Linköping University, Linköping SE-58185, Sweden
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, and SDHx respectively ( Welander et al . 2011 , Dahia 2014 ). In recent years, additional susceptibility genes for pheochromocytoma and paraganglioma have been discovered, including TMEM127 ( Qin et al . 2010 ), MAX ( Comino-Mendez et al
Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
Sector of Endocrinology Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
Department of Medical Genetics University of Cambridge, Cambridge, UK
Department of Surgery Erasmus MC, Rotterdam, The Netherlands
Division of Endocrinology Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Department of Medical Oncology Erasmus MC, Rotterdam, The Netherlands
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
Sector of Endocrinology Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
Department of Medical Genetics University of Cambridge, Cambridge, UK
Department of Surgery Erasmus MC, Rotterdam, The Netherlands
Division of Endocrinology Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Department of Medical Oncology Erasmus MC, Rotterdam, The Netherlands
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
Sector of Endocrinology Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
Department of Medical Genetics University of Cambridge, Cambridge, UK
Department of Surgery Erasmus MC, Rotterdam, The Netherlands
Division of Endocrinology Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Department of Medical Oncology Erasmus MC, Rotterdam, The Netherlands
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
Sector of Endocrinology Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
Department of Medical Genetics University of Cambridge, Cambridge, UK
Department of Surgery Erasmus MC, Rotterdam, The Netherlands
Division of Endocrinology Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Department of Medical Oncology Erasmus MC, Rotterdam, The Netherlands
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
Sector of Endocrinology Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
Department of Medical Genetics University of Cambridge, Cambridge, UK
Department of Surgery Erasmus MC, Rotterdam, The Netherlands
Division of Endocrinology Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Department of Medical Oncology Erasmus MC, Rotterdam, The Netherlands
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
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Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
Department of Medical Genetics University of Cambridge, Cambridge, UK
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
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Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
Department of Medical Genetics University of Cambridge, Cambridge, UK
Department of Surgery Erasmus MC, Rotterdam, The Netherlands
Division of Endocrinology Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Department of Medical Oncology Erasmus MC, Rotterdam, The Netherlands
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
Sector of Endocrinology Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
Department of Medical Genetics University of Cambridge, Cambridge, UK
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Division of Endocrinology Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
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Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
Department of Medical Genetics University of Cambridge, Cambridge, UK
Department of Surgery Erasmus MC, Rotterdam, The Netherlands
Division of Endocrinology Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Department of Medical Oncology Erasmus MC, Rotterdam, The Netherlands
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
Sector of Endocrinology Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
Department of Medical Genetics University of Cambridge, Cambridge, UK
Department of Surgery Erasmus MC, Rotterdam, The Netherlands
Division of Endocrinology Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
Sector of Endocrinology Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
Department of Medical Genetics University of Cambridge, Cambridge, UK
Department of Surgery Erasmus MC, Rotterdam, The Netherlands
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
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Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
Sector of Endocrinology Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
Department of Medical Genetics University of Cambridge, Cambridge, UK
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Division of Endocrinology Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
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Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
Sector of Endocrinology Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
Department of Medical Genetics University of Cambridge, Cambridge, UK
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Division of Endocrinology Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Department of Medical Oncology Erasmus MC, Rotterdam, The Netherlands
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
Sector of Endocrinology Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
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Department of Surgery Erasmus MC, Rotterdam, The Netherlands
Division of Endocrinology Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Department of Medical Oncology Erasmus MC, Rotterdam, The Netherlands
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
Department of Pathology Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands
Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
Sector of Endocrinology Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
Department of Medical Genetics University of Cambridge, Cambridge, UK
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
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Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
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Department of Pediatric Oncology–Hematology Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
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Cancer Biology and Metabolism Group Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK
Department of Medical Genetics University of Cambridge, Cambridge, UK
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peripheral neuroblastic tumors (Erasmus MC, Rotterdam, The Netherlands: 15 NBLs, eight ganglioneuroblastomas, and ten ganglioneuromas). Tumors with mutations in the SDH-x genes, such as SDHA , SDHB , SDHC , SDHD , and SDHAF2 , display loss of
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). Nineteen of the 58 cases (33%) were mutation-negative. Twenty-nine (50%) exhibited mutations in the SDHx cluster (predominantly SDHB : n = 25). The remaining samples exhibited individual mutations in PHEO/PGL-associated genes. Cluster 1-associated
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defined association. Carney–Stratakis syndrome is characterized by the association of GIST with paraganglioma and, in most cases is caused by mutations in SDHX genes ( McWhinney et al . 2007 , Janeway et al . 2011 ). Germline SDHX mutation may also be
University of Sydney, Sydney, New South Wales, Australia
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Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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University of Sydney, Sydney, New South Wales, Australia
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) and Polish ( n = 70) subsets; Table 2 and Supplementary Tables 1, 2, see section on supplementary materials given at the end of this article). As shown in Table 2, an additional 15 subjects (of whom five also had germline SDHx mutations) were
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germline mutation in one of the 20 PPGL susceptibility genes identified so far. Mutations in SDHx ( SDHA , SDHB , SDHC , SDHD , and SDHAF2 ) genes are the most frequently involved, causing approximately half of the genetically determined cases
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Section of Hematology/Oncology, Genomic Medicine Institute, Department of Genetics and Genome Sciences, Endocrine Surgery Research Program, Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
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mutations in other genes, such as succinate dehydrogenase genes ( SDHx ) (8%), PIK3CA (8.8%), AKT1 (2.2%), and SEC23B (4%) are also known as CS/CLS susceptibility genes ( Ni et al . 2008 , Ngeow et al . 2011 , Orloff et al . 2013 ). CS/CLS is one
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that 95% of the patients had PCC and 6% had PGL, all of which were sympathetic. Fourteen percent of the patients displayed bilateral PCC, 9% developed malignant disease, and the mean age at presentation was 42 years. SDHx Genes and protein functions SDH
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definition, we included only SDHB-negative tumors by IHC in the study because we were looking for genes mutated in SDHB-negative tumors that were negative for SDHx pathogenic variants. Also to be included in the study, all patients were SDHA , SDHB , SDHC
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SDHx genes ( Zantour et al . 2004 , Boedeker et al . 2009 ). Heritable non- SDHx paraganglioma can also occur in tumor syndromes mainly associated with pheochromocytomas such as von Hippel–Lindau disease (associated with mutations of the VHL gene