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Eamonn R Maher
Eamonn R Maher
Department of Medical Genetics, Department of Clinical Genetics, University of Cambridge, Cambridge, UK and
Department of Medical Genetics, Department of Clinical Genetics, University of Cambridge, Cambridge, UK and
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Department of Medical Genetics, Department of Clinical Genetics, University of Cambridge, Cambridge, UK and
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In this issue of Endocrine-Related Cancer, Toledo et al. report the identification of activating mutations in the HIF2 (EPAS1) transcription factor in a subset of sporadic pheochromocytomas and paragangliomas. These findings add significantly to an evolving and complex story of the role of hypoxic gene response pathways in human endocrine neoplasia.
Emma R Woodward
Emma R Woodward
Section of Medical and Molecular Genetics and Cancer Research UK Renal Molecular Oncology Group, University of Birmingham, Institute of Biomedical Research, Birmingham B15 2TT, UK and West Midlands Regional Genetics Service, Birmingham Women’s Hospital, Birmingham B15 2TG, UK
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Eamonn R Maher
Eamonn R Maher
Section of Medical and Molecular Genetics and Cancer Research UK Renal Molecular Oncology Group, University of Birmingham, Institute of Biomedical Research, Birmingham B15 2TT, UK and West Midlands Regional Genetics Service, Birmingham Women’s Hospital, Birmingham B15 2TG, UK
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Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome caused by mutations in the VHL tumour suppressor gene. VHL disease is characterised by marked phenotypic variability and the most common tumours are haemangioblastomas of the retina and central nervous system and clear cell renal cell carcinoma. However, endocrine tumours, most commonly phaeochromocytoma and non-secretory pancreatic islet cell cancers, demonstrate marked interfamilial variations in frequency and are significant causes of morbidity and, sometimes, mortality. Genotype–phenotype correlations have revealed that certain missense mutations are associated with a high risk of phaeochromocytoma but total loss of function mutations are associated with a low risk. Furthermore, rare mutations may predispose to a phaeochromocytoma-only phenotype. Germline VHL mutations may be detected in 5–11% of all phaeochromocytoma cases and mutation analysis of VHL and other phaeochromocytoma susceptibility genes (SDHB, SDHD and RET) should be performed in all cases of familial, multiple or early onset phaeochromocytomas, and considered in other cases. The VHL gene product has a key role in regulating the stability of hypoxia-inducible factors (HIF-1 and HIF-2) such that inactivation of VHL leads to up-regulation of HIF-1 and HIF-2 protein expression and activation of hypoxic gene response pathways. Germline SDHB and SDHD mutations also lead to increased expression of HIF target genes, but it appears that phaeochromocytoma susceptibility in VHL disease cannot be attributed to HIF activation alone. Recently, it has been suggested that an HIF-independent failure of developmental apoptosis is a common feature of all inherited phaeochromocytoma susceptibility syndromes.
Bora E Baysal
Bora E Baysal
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Eamonn R Maher
Eamonn R Maher
Department of Pathology, Department of Medical Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA
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Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine neoplasms that derive from small paraganglionic tissues which are located from skull base to the pelvic floor. Genetic predisposition plays an important role in development of PPGLs. Since the discovery of first mutations in the succinate dehydrogenase D (SDHD) gene, which encodes the smallest subunit of mitochondrial complex II (SDH), genetic studies have revealed a major role for mutations in SDH subunit genes, primarily in SDHB and SDHD, in predisposition to both familial and non-familial PPGLs. SDH-mutated PPGLs show robust expression of hypoxia induced genes, and genomic and histone hypermethylation. These effects occur in part through succinate-mediated inhibition of α-ketoglutarate-dependent dioxygenases. However, details of mechanisms by which SDH mutations activate hypoxic pathways and trigger subsequent neoplastic transformation remain poorly understood. Here, we present a brief review of the genetic and mechanistic aspects of SDH-mutated PPGLs.
Ruth T Casey
Ruth T Casey
Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre, Cambridge, UK
Department of Endocrinology, Cambridge University NHS Foundation Trust, Cambridge, UK
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Department of Endocrinology, Cambridge University NHS Foundation Trust, Cambridge, UK
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Benjamin G Challis
Benjamin G Challis
Department of Endocrinology, Cambridge University NHS Foundation Trust, Cambridge, UK
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Alison Marker
Alison Marker
Department of Histopathology, Cambridge University NHS Foundation Trust, Cambridge, UK
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Deborah Pitfield
Deborah Pitfield
Department of Endocrinology, Cambridge University NHS Foundation Trust, Cambridge, UK
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Heok K Cheow
Heok K Cheow
Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Ashley Shaw
Ashley Shaw
Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Soo-Mi Park
Soo-Mi Park
Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre, Cambridge, UK
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Helen L Simpson
Helen L Simpson
Department of Diabetes and Endocrinology, University College London Hospitals, NHS Foundation Trust, London, UK
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Eamonn R Maher
Eamonn R Maher
Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre, Cambridge, UK
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Caroline D E Margetts
Caroline D E Margetts
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Mark Morris
Mark Morris
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Dewi Astuti
Dewi Astuti
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Dean C Gentle
Dean C Gentle
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Alberto Cascon
Alberto Cascon
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Fiona E McRonald
Fiona E McRonald
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Daniel Catchpoole
Daniel Catchpoole
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Mercedes Robledo
Mercedes Robledo
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Hartmut P H Neumann
Hartmut P H Neumann
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Farida Latif
Farida Latif
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Eamonn R Maher
Eamonn R Maher
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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The molecular genetics of inherited phaeochromocytoma have received considerable attention, but the somatic genetic and epigenetic events that characterise tumourigenesis in sporadic phaeochromocytomas are less well defined. Previously, we found considerable overlap between patterns of promoter region tumour suppressor gene (TSG) hypermethylation in two neural crest tumours, neuroblastoma and phaeochromocytoma. In order to identify candidate biomarkers and epigenetically inactivated TSGs in phaeochromocytoma and neuroblastoma, we characterised changes in gene expression in three neuroblastoma cell lines after treatment with the demethylating agent 5-azacytidine. Promoter region methylation status was then determined for 28 genes that demonstrated increased expression after demethylation. Three genes HSP47, homeobox A9 (HOXA9) and opioid binding protein (OPCML) were methylated in >10% of phaeochromocytomas (52, 17 and 12% respectively). Two of the genes, epithelial membrane protein 3 (EMP3) and HSP47, demonstrated significantly more frequent methylation in neuroblastoma than phaeochromocytoma. These findings extend epigenotype of phaeochromocytoma and identify candidate genes implicated in sporadic phaeochromocytoma tumourigenesis.
Dewi Astuti
Dewi Astuti
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Christopher J Ricketts
Christopher J Ricketts
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Rasheduzzaman Chowdhury
Rasheduzzaman Chowdhury
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Michael A McDonough
Michael A McDonough
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Dean Gentle
Dean Gentle
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Gail Kirby
Gail Kirby
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Susanne Schlisio
Susanne Schlisio
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Rajappa S Kenchappa
Rajappa S Kenchappa
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Bruce D Carter
Bruce D Carter
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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William G Kaelin Jr
William G Kaelin Jr
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Peter J Ratcliffe
Peter J Ratcliffe
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Christopher J Schofield
Christopher J Schofield
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Farida Latif
Farida Latif
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Eamonn R Maher
Eamonn R Maher
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
Centre for Rare Diseases and Personalised Medicine, CRUK Renal Molecular Oncology Group, Chemistry Research Laboratory, Howard Hughes Medical Institute, Oxygen Sensing and Cancer Laboratory, Department of Biochemistry and Center for Molecular Neuroscience, Henry Wellcome Building for Molecular Physiology, West Midlands Regional Genetics Service, University of Birmingham, Birmingham B15 2TT, UK
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Germline mutations in the von Hippel–Lindau disease (VHL) and succinate dehydrogenase subunit B (SDHB) genes can cause inherited phaeochromocytoma and/or renal cell carcinoma (RCC). Dysregulation of the hypoxia-inducible factor (HIF) transcription factors has been linked to VHL and SDHB-related RCC; both HIF dysregulation and disordered function of a prolyl hydroxylase domain isoform 3 (PHD3/EGLN3)-related pathway of neuronal apoptosis have been linked to the development of phaeochromocytoma. The 2-oxoglutarate-dependent prolyl hydroxylase enzymes PHD1 (EGLN2), PHD2 (EGLN1) and PHD3 (EGLN3) have a key role in regulating the stability of HIF-α subunits (and hence expression of the HIF-α transcription factors). A germline PHD2 mutation has been reported in association with congenital erythrocytosis and recurrent extra-adrenal phaeochromocytoma. We undertook mutation analysis of PHD1, PHD2 and PHD3 in two cohorts of patients with features of inherited phaeochromocytoma (n=82) and inherited RCC (n=64) and no evidence of germline mutations in known susceptibility genes. No confirmed pathogenic mutations were detected suggesting that mutations in these genes are not a frequent cause of inherited phaeochromocytoma or RCC.
Florian Haller
Florian Haller
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Evgeny A Moskalev
Evgeny A Moskalev
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Fabio R Faucz
Fabio R Faucz
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Sarah Barthelmeß
Sarah Barthelmeß
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Stefan Wiemann
Stefan Wiemann
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Matthias Bieg
Matthias Bieg
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Guillaume Assie
Guillaume Assie
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Jerome Bertherat
Jerome Bertherat
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Inga-Marie Schaefer
Inga-Marie Schaefer
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Claudia Otto
Claudia Otto
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Eleanor Rattenberry
Eleanor Rattenberry
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Eamonn R Maher
Eamonn R Maher
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Philipp Ströbel
Philipp Ströbel
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Martin Werner
Martin Werner
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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J Aidan Carney
J Aidan Carney
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Arndt Hartmann
Arndt Hartmann
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Constantine A Stratakis
Constantine A Stratakis
Institute of Pathology University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Krankenhausstraße 8-10, D-91054 Erlangen, Germany
Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Program on Developmental Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
Division Molecular Genome Analysis
Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ), Heidelberg, Germany
Institut Cochin INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
Department of Endocrinology Referal Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
Institute of Pathology University Medical Center, Georg‐August University, Göttingen, Germany
Institute of Pathology University Hospital, Albert‐Ludwigs University Freiburg, Freiburg, Germany
School of Clinical and Experimental Medicine College of Medical and Dental Sciences, Centre for Rare Diseases and Personalised Medicine, Birmingham Women's Hospital, University of Birmingham and West Midlands Regional Genetics Service, Birmingham, UK
Department of Medical Genetics University of Cambridge, Cambridge CB2 0QQ, UK
Laboratory Medicine and Pathology Emeritus Staff, Mayo Clinic, Rochester, Minnesota, USA
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Abbas Agaimy
Abbas Agaimy
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Carney triad (CT) is a rare condition with synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs), paragangliomas (PGLs), and pulmonary chondromas in a patient. In contrast to Carney–Stratakis syndrome (CSS) and familial PGL syndromes, no germline or somatic mutations in the succinate dehydrogenase (SDH) complex subunits A, B, C, or D have been found in most tumors and/or patients with CT. Nonetheless, the tumors arising among patients with CT, CSS, or familial PGL share a similar morphology with loss of the SDHB subunit on the protein level. For the current study, we employed massive parallel bisulfite sequencing to evaluate DNA methylation patterns in CpG islands in proximity to the gene loci of all four SDH subunits. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of SDHC in tumors of patients with CT, which was not present in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. This DNA methylation pattern was correlated to a reduced mRNA expression of SDHC, and concurrent loss of the SDHC subunit on the protein level. Collectively, these data suggest epigenetic inactivation of the SDHC gene locus with functional impairment of the SDH complex as a plausible alternate mechanism of tumorigenesis in CT.
Thomas G Papathomas
Thomas G Papathomas
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Lindsey Oudijk
Lindsey Oudijk
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Ellen C Zwarthoff
Ellen C Zwarthoff
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Edward Post
Edward Post
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Floor A Duijkers
Floor A Duijkers
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Max M van Noesel
Max M van Noesel
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Leo J Hofland
Leo J Hofland
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Patrick J Pollard
Patrick J Pollard
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Eamonn R Maher
Eamonn R Maher
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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David F Restuccia
David F Restuccia
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Richard A Feelders
Richard A Feelders
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Gaston J H Franssen
Gaston J H Franssen
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Henri J Timmers
Henri J Timmers
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Stefan Sleijfer
Stefan Sleijfer
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Wouter W de Herder
Wouter W de Herder
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Ronald R de Krijger
Ronald R de Krijger
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
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
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
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
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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Winand N M Dinjens
Winand N M Dinjens
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Esther Korpershoek
Esther Korpershoek
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
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
Department of Pathology Reinier de Graaf Hospital, Delft, The Netherlands
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Hotspot mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been recently reported in human cancers and proposed as a novel mechanism of telomerase activation. To explore TERT promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia, a set of 253 tumors (38 adrenocortical carcinomas (ACCs), 127 pheochromocytomas (PCCs), 18 extra-adrenal paragangliomas (ea PGLs), 37 head and neck PGLs (HN PGLs), and 33 peripheral neuroblastic tumors) was selected along with 16 human neuroblastoma (NBL) and two ACC cell lines to assess TERT promoter mutations by the Sanger sequencing method. All mutations detected were confirmed by a SNaPshot assay. Additionally, 36 gastrointestinal stromal tumors (GISTs) were added to explore an association between TERT promoter mutations and SDH deficiency. TERT promoter mutations were found in seven out of 289 tumors and in three out of 18 human cell lines; four C228T mutations in 38 ACCs (10.5%), two C228T mutations in 18 ea PGLs (11.1%), one C250T mutation in 36 GISTs (2.8%), and three C228T mutations in 16 human NBL cell lines (18.75%). No mutation was detected in PCCs, HN PGLs, neuroblastic tumors as well as ACC cell lines. TERT promoter mutations preferentially occurred in a SDH-deficient setting (P=0.01) being present in three out of 47 (6.4%) SDH-deficient tumors vs zero out of 171 (0%) SDH-intact tumors. We conclude that TERT promoter mutations occur in ACCs and ea PGLs. In addition, preliminary evidence indicates a potential association with the acquisition of TERT promoter mutations in SDH-deficient tumors.
Umasuthan Srirangalingam
Umasuthan Srirangalingam
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Bernard Khoo
Bernard Khoo
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Lisa Walker
Lisa Walker
Department of Endocrinology, Department of Clinical Genetics, Department of Medical and Molecular Genetics, Department of Medicine, Department of Medicine, Oncology Centre, Henry Wellcome Building for Molecular Physiology, Radiation Oncology, Center for Cancer Imaging, Cellular Pathology, Clinical Biochemistry, Clinical Genetics, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK
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Fiona MacDonald
Fiona MacDonald
Department of Endocrinology, Department of Clinical Genetics, Department of Medical and Molecular Genetics, Department of Medicine, Department of Medicine, Oncology Centre, Henry Wellcome Building for Molecular Physiology, Radiation Oncology, Center for Cancer Imaging, Cellular Pathology, Clinical Biochemistry, Clinical Genetics, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK
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Robert H Skelly
Robert H Skelly
Department of Endocrinology, Department of Clinical Genetics, Department of Medical and Molecular Genetics, Department of Medicine, Department of Medicine, Oncology Centre, Henry Wellcome Building for Molecular Physiology, Radiation Oncology, Center for Cancer Imaging, Cellular Pathology, Clinical Biochemistry, Clinical Genetics, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK
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Emad George
Emad George
Department of Endocrinology, Department of Clinical Genetics, Department of Medical and Molecular Genetics, Department of Medicine, Department of Medicine, Oncology Centre, Henry Wellcome Building for Molecular Physiology, Radiation Oncology, Center for Cancer Imaging, Cellular Pathology, Clinical Biochemistry, Clinical Genetics, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK
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David Spooner
David Spooner
Department of Endocrinology, Department of Clinical Genetics, Department of Medical and Molecular Genetics, Department of Medicine, Department of Medicine, Oncology Centre, Henry Wellcome Building for Molecular Physiology, Radiation Oncology, Center for Cancer Imaging, Cellular Pathology, Clinical Biochemistry, Clinical Genetics, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK
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Linda B Johnston
Linda B Johnston
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John P Monson
John P Monson
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Ashley B Grossman
Ashley B Grossman
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W M Drake
W M Drake
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Scott A Akker
Scott A Akker
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Patrick J Pollard
Patrick J Pollard
Department of Endocrinology, Department of Clinical Genetics, Department of Medical and Molecular Genetics, Department of Medicine, Department of Medicine, Oncology Centre, Henry Wellcome Building for Molecular Physiology, Radiation Oncology, Center for Cancer Imaging, Cellular Pathology, Clinical Biochemistry, Clinical Genetics, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK
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Nick Plowman
Nick Plowman
Department of Endocrinology, Department of Clinical Genetics, Department of Medical and Molecular Genetics, Department of Medicine, Department of Medicine, Oncology Centre, Henry Wellcome Building for Molecular Physiology, Radiation Oncology, Center for Cancer Imaging, Cellular Pathology, Clinical Biochemistry, Clinical Genetics, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK
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Norbert Avril
Norbert Avril
Department of Endocrinology, Department of Clinical Genetics, Department of Medical and Molecular Genetics, Department of Medicine, Department of Medicine, Oncology Centre, Henry Wellcome Building for Molecular Physiology, Radiation Oncology, Center for Cancer Imaging, Cellular Pathology, Clinical Biochemistry, Clinical Genetics, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK
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Daniel M Berney
Daniel M Berney
Department of Endocrinology, Department of Clinical Genetics, Department of Medical and Molecular Genetics, Department of Medicine, Department of Medicine, Oncology Centre, Henry Wellcome Building for Molecular Physiology, Radiation Oncology, Center for Cancer Imaging, Cellular Pathology, Clinical Biochemistry, Clinical Genetics, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK
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Jacky M Burrin
Jacky M Burrin
Department of Endocrinology, Department of Clinical Genetics, Department of Medical and Molecular Genetics, Department of Medicine, Department of Medicine, Oncology Centre, Henry Wellcome Building for Molecular Physiology, Radiation Oncology, Center for Cancer Imaging, Cellular Pathology, Clinical Biochemistry, Clinical Genetics, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK
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Rodney H Reznek
Rodney H Reznek
Department of Endocrinology, Department of Clinical Genetics, Department of Medical and Molecular Genetics, Department of Medicine, Department of Medicine, Oncology Centre, Henry Wellcome Building for Molecular Physiology, Radiation Oncology, Center for Cancer Imaging, Cellular Pathology, Clinical Biochemistry, Clinical Genetics, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK
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V K Ajith Kumar
V K Ajith Kumar
Department of Endocrinology, Department of Clinical Genetics, Department of Medical and Molecular Genetics, Department of Medicine, Department of Medicine, Oncology Centre, Henry Wellcome Building for Molecular Physiology, Radiation Oncology, Center for Cancer Imaging, Cellular Pathology, Clinical Biochemistry, Clinical Genetics, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK
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Eamonn R Maher
Eamonn R Maher
Department of Endocrinology, Department of Clinical Genetics, Department of Medical and Molecular Genetics, Department of Medicine, Department of Medicine, Oncology Centre, Henry Wellcome Building for Molecular Physiology, Radiation Oncology, Center for Cancer Imaging, Cellular Pathology, Clinical Biochemistry, Clinical Genetics, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK
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Shern L Chew
Shern L Chew
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Mutations in succinate dehydrogense-B (SDHB) and the von Hippel-Lindau (VHL) genes result in an increased risk of developing chromaffin tumours via a common aetiological pathway. The aim of the present retrospective study was to compare the clinical phenotypes of disease in subjects developing chromaffin tumours as a result of SDHB mutations or VHL disease. Thirty-one subjects with chromaffin tumours were assessed; 16 subjects had SDHB gene mutations and 15 subjects had a diagnosis of VHL. VHL-related tumours were predominantly adrenal phaeochromocytomas (22/26; 84.6%), while SDHB-related tumours were predominantly extra-adrenal paragangliomas (19/25; 76%). Median age at onset of the first chromaffin tumour was similar in the two cohorts. Tumour size was significantly larger in the SDHB cohort in comparison with the VHL cohort (P=0.002). Multifocal disease was present in 9/15 (60%) of the VHL cohort (bilateral phaeochromocytomas) and only 3/16 (19%) of the SDHB cohort, while metastatic disease was found in 5/16 (31%) of the SDHB cohort but not in the VHL cohort to date. The frequency of symptoms, hypertension and the magnitude of catecholamine secretion appeared to be greater in the SDHB cohort. Renal cell carcinomas were a feature in 5/15 (33%) of the VHL cohort and 1/16 (6%) of the SDHB cohort. These data indicate that SDHB-related tumours are predominantly extra-adrenal in location and associated with higher catecholamine secretion and more malignant disease, in subjects who appear more symptomatic. VHL-related tumours tend to be adrenal phaeochromocytomas, frequently bilateral and associated with a milder phenotype.
