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Karel Pacak Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

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Roderick Clifton-Bligh Department of Endocrinology Royal North Shore Hospital, University of Sydney, Australia

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Pheochromocytomas and paragangliomas (PPGLs) are defined as neuroendocrine tumors that produce catecholamines. Many recent advances in their management, localization, treatment, as well as surveillance have significantly improved outcomes for patients with PPGLs or carriers of pathogenic genetic variants linked to the development of these tumors. At present, those advances mainly include the molecular stratification of PPGLs into seven clusters, the 2017 WHO revised definition of these tumors, the presence of specific clinical features pointing toward PPGL, the use of plasma metanephrines and 3-methoxytyramine with specific reference limits to assess the likelihood of having a PPGL (e.g. patients at high and low risk) including age-specific reference limits, nuclear medicine guidelines outlining cluster- and metastatic disease-specific functional (here mainly positron emission tomography and metaiodobenzylguanidine scintigraphy) imaging in the precise diagnostic localization of PPGLs, the guidelines for using radio- vs chemotherapy for patients with metastatic disease, and the international consensus on initial screening and follow-up of asymptomatic germline SDHx pathogenic variant carriers. Furthermore, new collaborative efforts particularly based on multi-institutional and worldwide initiatives are now considered key forces in improving our understanding and knowledge about these tumors and future successful treatments or even preventative interventions.

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Judith Favier Université Paris Cité, Inserm UMR970 PARCC, Equipe Labellisée par la Ligue contre le cancer, Paris, France

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Karel Pacak Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

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Roderick Clifton-Bligh Department of Endocrinology Royal North Shore Hospital, University of Sydney, Sydney, Australia

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Diana E Benn Cancer Genetics, Kolling Institute, Royal North Shore Hospital, University of Sydney, St Leonards, New South Wales 2065, Australia

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Bruce G Robinson Cancer Genetics, Kolling Institute, Royal North Shore Hospital, University of Sydney, St Leonards, New South Wales 2065, Australia

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Roderick J Clifton-Bligh Cancer Genetics, Kolling Institute, Royal North Shore Hospital, University of Sydney, St Leonards, New South Wales 2065, Australia

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The paraganglioma (PGL) syndromes types 1–5 are autosomal dominant disorders characterized by familial predisposition to PGLs, phaeochromocytomas (PCs), renal cell cancers, gastrointestinal stromal tumours and, rarely, pituitary adenomas. Each syndrome is associated with mutation in a gene encoding a particular subunit (or assembly factor) of succinate dehydrogenase (SDHx). The clinical manifestations of these syndromes are protean: patients may present with features of catecholamine excess (including the classic triad of headache, sweating and palpitations), or with symptoms from local tumour mass, or increasingly as an incidental finding on imaging performed for some other purpose. As genetic testing for these syndromes becomes more widespread, presymptomatic diagnosis is also possible, although penetrance of disease in these syndromes is highly variable and tumour development does not clearly follow a predetermined pattern. PGL1 syndrome (SDHD) and PGL2 syndrome (SDHAF2) are notable for high frequency of multifocal tumour development and for parent-of-origin inheritance: disease is almost only ever manifest in subjects inheriting the defective allele from their father. PGL4 syndrome (SDHB) is notable for an increased risk of malignant PGL or PC. PGL3 syndrome (SDHC) and PGL5 syndrome (SDHA) are less common and appear to be associated with lower penetrance of tumour development. Although these syndromes are all associated with SDH deficiency, few genotype–phenotype relationships have yet been established, and indeed it is remarkable that such divergent phenotypes can arise from disruption of a common molecular pathway. This article reviews the clinical presentations of these syndromes, including their component tumours and underlying genetic basis.

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Alexander J Cole Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, New South Wales 2065, Australia

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Roderick Clifton-Bligh Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, New South Wales 2065, Australia

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Deborah J Marsh Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, New South Wales 2065, Australia

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Ubiquitination has traditionally been viewed in the context of polyubiquitination that is essential for marking proteins for degradation via the proteasome. Recent discoveries have shed light on key cellular roles for monoubiquitination, including as a post-translational modification (PTM) of histones such as histone H2B. Monoubiquitination plays a significant role as one of the largest histone PTMs, alongside smaller, better-studied modifications such as methylation, acetylation and phosphorylation. Monoubiquitination of histone H2B at lysine 120 (H2Bub1) has been shown to have key roles in transcription, the DNA damage response and stem cell differentiation. The H2Bub1 enzymatic cascade involves E3 RING finger ubiquitin ligases, with the main E3 generally accepted to be the RNF20–RNF40 complex, and deubiquitinases including ubiquitin-specific protease 7 (USP7), USP22 and USP44. H2Bub1 has been shown to physically disrupt chromatin strands, fostering a more open chromatin structure accessible to transcription factors and DNA repair proteins. It also acts as a recruiting signal, actively attracting proteins with roles in transcription and DNA damage. H2Bub1 also appears to play central roles in histone cross-talk, influencing methylation events on histone H3, including H3K4 and H3K79. Most significantly, global levels of H2Bub1 are low to absent in advanced cancers including breast, colorectal, lung and parathyroid, marking H2Bub1 and the enzymes that regulate it as key molecules of interest as possible new therapeutic targets for the treatment of cancer. This review offers an overview of current knowledge regarding H2Bub1 and highlights links between dysregulation of H2Bub1-associated enzymes, stem cells and malignancy.

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Venessa H M Tsang Department of Endocrinology, Royal North Shore Hospital, St Leonards, Sydney, Australia
Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia

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Matti Gild Department of Endocrinology, Royal North Shore Hospital, St Leonards, Sydney, Australia
Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
Cancer Genetics Laboratory, Kolling Institute of Medical Research, Sydney, Australia

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Anthony Glover Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
Department of Endocrine Surgery, Royal North Shore Hospital, St Leonards, Sydney, Australia

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Roderick Clifton-Bligh Department of Endocrinology, Royal North Shore Hospital, St Leonards, Sydney, Australia
Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
Cancer Genetics Laboratory, Kolling Institute of Medical Research, Sydney, Australia

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Bruce G Robinson Department of Endocrinology, Royal North Shore Hospital, St Leonards, Sydney, Australia
Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
Cancer Genetics Laboratory, Kolling Institute of Medical Research, Sydney, Australia

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COVID-19 has modified the way we practice medicine. For thyroid cancer, there have been several significant impacts. First, the diagnosis has been delayed due to social isolation, reduced access to investigations and staff redeployment. Secondly, treatment planning has needed to take into account the risk to patients and/or staff of nosocomial transmission of the virus. Finally, there are some specific concerns with respect to interactions between the virus, its treatments and cancer. This mini-review aims to address each of these impacts and to provide some guidance and confidence to our patients and colleagues during this challenging time.

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Susan Richter Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany

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Timothy J Garrett Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA

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Nicole Bechmann Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany

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Roderick J Clifton-Bligh Cancer Genetics Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, Australia
Department of Endocrinology, Royal North Shore Hospital, St Leonards, Australia

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Hans K Ghayee Department of Internal Medicine, Division of Endocrinology, University of Florida College of Medicine and Malcom Randall VA Medical Center, Gainesville, Florida, USA

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Metabolites represent the highest layer of biological information. Their diverse chemical nature enables networks of chemical reactions that are critical for maintaining life by providing energy and building blocks. Quantification by targeted and untargeted analytical methods using either mass spectrometry or nuclear magnetic resonance spectroscopy has been applied to pheochromocytoma/paraganglioma (PPGL) with the long-term goal to improve diagnosis and therapy. PPGLs have unique features that provide useful biomarkers and clues for targeted treatments. First, high production rates of catecholamines and metanephrines allow for specific and sensitive detection of the disease in plasma or urine. Secondly, PPGLs are associated with heritable pathogenic variants (PVs) in around 40% of cases, many of which occur in genes encoding enzymes, such as succinate dehydrogenase (SDH) and fumarate hydratase (FH). These genetic aberrations lead to the overproduction of oncometabolites succinate or fumarate, respectively, and are detectable in tumors and blood. Such metabolic dysregulation can be exploited diagnostically, with the aim to ensure appropriate interpretation of gene variants, especially those with unknown significance, and facilitate early tumor detection through regular patient follow-up. Furthermore, SDHx and FH PV alter cellular pathways, including DNA hypermethylation, hypoxia signaling, redox homeostasis, DNA repair, calcium signaling, kinase cascades, and central carbon metabolism. Pharmacological interventions targeted toward such features have the potential to uncover treatments against metastatic PPGL, around 50% of which are associated with germline PV in SDHx. With the availability of omics technologies for all layers of biological information, personalized diagnostics and treatment is in close reach.

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Patricia L M Dahia Division of Hematology and Medical Oncology, Department of Medicine, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

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Roderick Clifton-Bligh Department of Endocrinology, Royal North Shore Hospital, Northern Clinical School, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia

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Anne-Paule Gimenez-Roqueplo AP-HP, Hôpital Européen Georges Pompidou, Genetics Department, Paris, France
Human Cancer Genetics Program, Spanish National Cancer Research Center, Madrid, Spain

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Mercedes Robledo AP-HP, Hôpital Européen Georges Pompidou, Genetics Department, Paris, France
Human Cancer Genetics Program, Spanish National Cancer Research Center, Madrid, Spain

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Camilo Jimenez Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

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Pheochromocytomas and paragangliomas (PPGLs) are adrenal or extra-adrenal autonomous nervous system-derived tumors. Most PPGLs are benign, but approximately 15% progress with metastases (mPPGLs). mPPGLs are more likely to occur in patients with large pheochromocytomas, sympathetic paragangliomas, and norepinephrine-secreting tumors. Older subjects, those with larger tumors and synchronous metastases, advance more rapidly. Germline mutations of SDHB, FH, and possibly SLC25A11, or somatic MAML3 disruptions relate to a higher risk for metastatic disease. However, it is unclear whether these mutations predict outcome. Once diagnosed, there are no well-established predictors of outcome in mPPGLs, and aggressive tumors have few therapeutic options and limited response. High-specific activity (HSA) metaiodine-benzyl-guanidine (MIBG) is the first FDA approved treatment and shows clinical effectiveness for MIBG-avid mPPGLs. Ongoing and future investigations should involve validation of emerging candidate outcome biomarkers, including somatic ATRX, TERT, and microRNA disruptions and identification of novel prognostic indicators. Long-term effect of HSA-MIBG and the role of other radiopharmaceuticals should be investigated. Novel trials targeting molecular events prevalent in SDHB/FH mutant tumors, such as activated hypoxia inducible factor 2 (HIF2), angiogenesis, or other mitochondrial defects that might confer unique vulnerability to these tumors should be developed and initiated. As therapeutic options are anticipated to expand, multi-institutional collaborations and well-defined clinical and molecular endpoints will be critical to achieve higher success rates in improving care for patients with mPPGLs.

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Jia-Jing Lee Department of Molecular Medicine and Surgery, Department of Oncology-Pathology, Kolling Institute of Medical Research, Department of Oncology, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden
Department of Molecular Medicine and Surgery, Department of Oncology-Pathology, Kolling Institute of Medical Research, Department of Oncology, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden

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Amy Y M Au Department of Molecular Medicine and Surgery, Department of Oncology-Pathology, Kolling Institute of Medical Research, Department of Oncology, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden

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Theodoros Foukakis Department of Molecular Medicine and Surgery, Department of Oncology-Pathology, Kolling Institute of Medical Research, Department of Oncology, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden

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Michela Barbaro Department of Molecular Medicine and Surgery, Department of Oncology-Pathology, Kolling Institute of Medical Research, Department of Oncology, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden

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Nimrod Kiss Department of Molecular Medicine and Surgery, Department of Oncology-Pathology, Kolling Institute of Medical Research, Department of Oncology, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden

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Roderick Clifton-Bligh Department of Molecular Medicine and Surgery, Department of Oncology-Pathology, Kolling Institute of Medical Research, Department of Oncology, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden

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Johan Staaf Department of Molecular Medicine and Surgery, Department of Oncology-Pathology, Kolling Institute of Medical Research, Department of Oncology, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden

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Åke Borg Department of Molecular Medicine and Surgery, Department of Oncology-Pathology, Kolling Institute of Medical Research, Department of Oncology, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden

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Leigh Delbridge Department of Molecular Medicine and Surgery, Department of Oncology-Pathology, Kolling Institute of Medical Research, Department of Oncology, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden

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Bruce G Robinson Department of Molecular Medicine and Surgery, Department of Oncology-Pathology, Kolling Institute of Medical Research, Department of Oncology, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden

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Göran Wallin Department of Molecular Medicine and Surgery, Department of Oncology-Pathology, Kolling Institute of Medical Research, Department of Oncology, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden

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Anders Höög Department of Molecular Medicine and Surgery, Department of Oncology-Pathology, Kolling Institute of Medical Research, Department of Oncology, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden

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Catharina Larsson Department of Molecular Medicine and Surgery, Department of Oncology-Pathology, Kolling Institute of Medical Research, Department of Oncology, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden

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Anaplastic thyroid cancer (ATC) is a rare but highly aggressive disease with largely unexplained etiology and molecular pathogenesis. In this study, we analyzed genome-wide copy number changes, BRAF (V-raf sarcoma viral oncogene homolog B1) mutations, and p16 and cyclin D1 expressions in a panel of ATC primary tumors. Three ATCs harbored the common BRAF mutation V600E. Using array-comparative genomic hybridisation (array-CGH), several distinct recurrent copy number alterations were revealed including gains in 16p11.2, 20q11.2, and 20q13.12. Subsequent fluorescence in situ hybridization revealed recurrent locus gain of UBCH10 in 20q13.12 and Cyclin D1 (CCND1) in 11q13. The detection of a homozygous loss encompassing the CDKN2A locus in 9p21.3 motivated the examination of p16 protein expression, which was undetectable in 24/27 ATCs (89%). Based on the frequent gain in 11q13 (41%; n=11), the role of CCND1 was further investigated. Expression of cyclin D1 protein was observed at varying levels in 18/27 ATCs (67%). The effect of CCND1 on thyroid cell proliferation was assessed in vitro in ATC cells by means of siRNA and in thyroid cells after CCND1 transfection. In summary, the recurrent chromosomal copy number changes and molecular alterations identified in this study may provide an insight into the pathogenesis and development of ATC.

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Dahlia F Davidoff Cancer Genetics, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia
University of Sydney, Camperdown, New South Wales, Australia
Department of Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, Australia

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Eugénie S Lim Department of Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK
Department of Endocrinology, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK

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Diana E Benn Cancer Genetics, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia
University of Sydney, Camperdown, New South Wales, Australia

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Yuvanaa Subramaniam Department of Endocrinology, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK

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Eleanor Dorman Department of Endocrinology, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK

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John R Burgess Department of Diabetes and Endocrinology, Royal Hobart Hospital, Hobart, Tasmania, Australia
School of Medicine, University of Tasmania, Hobart, Tasmania, Australia

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Scott A Akker Department of Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK
Department of Endocrinology, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK

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Roderick J Clifton-Bligh Cancer Genetics, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia
University of Sydney, Camperdown, New South Wales, Australia
Department of Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, Australia

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Phaeochromocytoma and paraganglioma are highly heritable tumours; half of those associated with a germline mutation are caused by mutations in genes for Krebs’s cycle enzymes, including succinate dehydrogenase (SDH). Inheritance of SDH alleles is assumed to be Mendelian (probability of 50% from each parent). The departure from transmission of parental alleles in a ratio of 1:1 is termed transmission ratio distortion (TRD). We sought to assess whether TRD occurs in the transmission of SDHB pathogenic variants (PVs). This study was conducted with 41 families of a discovery cohort from Royal North Shore Hospital, Australia, and 41 families from a validation cohort from St. Bartholomew’s Hospital, United Kingdom (UK). Inclusion criteria were a clinically diagnosed SDHB PV and a pedigree available for at least two generations. TRD was assessed in 575 participants with the exact binomial test. The transmission ratio for SDHB PV was 0.59 (P = 0.005) in the discovery cohort, 0.67 (P < 0.001) in the validation cohort, and 0.63 (P < 0.001) in the combined cohort. No parent-of-origin effect was observed. TRD remained significant after adjusting for potential confounders: 0.67 (P < 0.001) excluding families with incomplete family size data; 0.58 (P < 0.001) when probands were excluded. TRD was also evident for SDHD PVs in a cohort of 81 patients from 13 families from the UK. The reason for TRD of SDHB and SDHD PVs is unknown, but we hypothesize a survival advantage selected during early embryogenesis. The existence of TRD for SDHB and SDHD has implications for reproductive counselling, and further research into the heterozygote state.

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Trisha Dwight Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia
University of Sydney, Sydney, New South Wales, Australia

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Edward Kim Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia
University of Sydney, Sydney, New South Wales, Australia

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Karine Bastard Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia
University of Sydney, Sydney, New South Wales, Australia

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Diana E Benn Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia
University of Sydney, Sydney, New South Wales, Australia

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Graeme Eisenhofer Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

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Susan Richter Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

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Massimo Mannelli Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

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Elena Rapizzi Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

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Aleksander Prejbisz Department of Hypertension, National Institute of Cardiology, Warsaw, Poland

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Mariola Pęczkowska Department of Hypertension, National Institute of Cardiology, Warsaw, Poland

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Karel Pacak National Institutes of Health, Bethesda, Maryland, USA

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Roderick Clifton-Bligh Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia
University of Sydney, Sydney, New South Wales, Australia
Department of Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, Australia

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Mosaic or somatic EPAS1 mutations are associated with a range of phenotypes including pheochromocytoma and/or paraganglioma (PPGL), polycythemia and somatostatinoma. The pathogenic potential of germline EPAS1 variants however is not well understood. We report a number of germline EPAS1 variants occurring in patients with PPGL, including a novel variant c.739C>A (p.Arg247Ser); a previously described variant c.1121T>A (p.Phe374Tyr); several rare variants, c.581A>G (p.His194Arg), c.2353C>A (p.Pro785Thr) and c.2365A>G (p.Ile789Val); a common variant c.2296A>C (p.Thr766Pro). We performed detailed functional studies to understand their pathogenic role in PPGL. In transient transfection studies, EPAS1/HIF-2α p.Arg247Ser, p.Phe374Tyr and p.Pro785Thr were all stable in normoxia. In co-immunoprecipitation assays, only the novel variant p.Arg247Ser showed diminished interaction with pVHL. A direct interaction between HIF-2α Arg247 and pVHL was confirmed in structural models. Transactivation was assessed by means of a HRE-containing reporter gene in transiently transfected cells, and significantly higher reporter activity was only observed with EPAS1/HIF-2α p.Phe374Tyr and p.Pro785Thr. In conclusion, three germline EPAS1 variants (c.739C>A (p.Arg247Ser), c.1121T>A (p.Phe374Tyr) and c.2353C>A (p.Pro785Thr)) all have some functional features in common with somatic activating mutations. Our findings suggest that these three germline variants are hypermorphic alleles that may act as modifiers to the expression of PPGLs.

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