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- Author: Trisha Dwight x
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Department of Endocrinology, Royal North Shore Hospital, Sydney, Australia
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Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
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Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
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Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
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Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, Sydney, Australia
Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
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Phaeochromocytomas and paragangliomas (collectively termed PPGL) are rare yet highly heritable neuroendocrine tumours, with over one-third of cases associated with germline pathogenic variants (PVs) in numerous genes. PVs in the succinate dehydrogenase subunit-A gene (SDHA) were initially implicated in hereditary PPGL in 2010, and SDHA has since become an important susceptibility gene accounting for up to 2.8% of cases. However, it remains poorly understood, particularly regarding the clinical nature of SDHA PPGL, rates of recurrence and metastasis, and the nature of metastatic disease. We present a narrative review of SDHA-related PPGL, covering pathophysiology, relevance to current clinical practice, and considerations for clinical genetics. We analyse a pool of 107 previously reported cases of SDHA-associated PPGL to highlight the spectrum of SDHA-related PPGL. Our analysis demonstrates that SDHA PPGL occurs across a wide age range (11–81 years) and affects men and women equally. SDHA PPGL typically presents as single tumours (91%), usually occurring in the head and neck (46%) or abdomen (43%, including 15% with phaeochromocytomas). Metastatic disease was reported in 25.5% of cases, with bone (82%) and lymph nodes (71%) being the most common sites of metastasis, often identified many years after the initial diagnosis. A family history of SDHA-related neoplasia was rare, reported in only 4% of cases. Understanding the clinical nature and risks associated with SDHA PVs is essential for facilitating the optimal management of patients and their families.
University of Sydney, Sydney, New South Wales, Australia
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University of Sydney, Sydney, New South Wales, Australia
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University of Sydney, Sydney, New South Wales, Australia
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University of Sydney, Sydney, New South Wales, Australia
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Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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University of Sydney, Sydney, New South Wales, Australia
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.
The University of Sydney, Sydney, New South Wales, Australia
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Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen N, Denmark
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The University of Sydney, Sydney, New South Wales, Australia
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Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
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The Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
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The University of Sydney, Sydney, New South Wales, Australia
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Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
The Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia
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Cancer Diagnosis and Pathology Group, Kolling Institute, Royal North Shore Hospital, Sydney, New South Wales, Australia
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The Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
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The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
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The University of Sydney, Sydney, New South Wales, Australia
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The Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
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Pheochromocytomas (PC) and paragangliomas (PGL) are endocrine tumors for which the genetic and clinicopathological features of metastatic progression remain incompletely understood. As a result, the risk of metastasis from a primary tumor cannot be predicted. Early diagnosis of individuals at high risk of developing metastases is clinically important and the identification of new biomarkers that are predictive of metastatic potential is of high value. Activation of TERT has been associated with a number of malignant tumors, including PC/PGL. However, the mechanism of TERT activation in the majority of PC/PGL remains unclear. As TERT promoter mutations occur rarely in PC/PGL, we hypothesized that other mechanisms – such as structural variations – may underlie TERT activation in these tumors. From 35 PC and four PGL, we identified three primary PCs that developed metastases with elevated TERT expression, each of which lacked TERT promoter mutations and promoter DNA methylation. Using whole genome sequencing, we identified somatic structural alterations proximal to the TERT locus in two of these tumors. In both tumors, the genomic rearrangements led to the positioning of super-enhancers proximal to the TERT promoter, that are likely responsible for the activation of the normally tightly repressed TERT expression in chromaffin cells
