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      Update of Pheochromocytoma Syndromes: Genetics, Biochemical Evaluation, and Imaging

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          Abstract

          Pheochromocytomas and paragangliomas (PCCs/PGLs) are rare commonly benign neuroendocrine tumors that share pathology features and clinical behavior in many cases. While PCCs are chromaffin-derived tumors that arise within the adrenal medulla, PGLs are neural-crest-derived tumors that originate at the extraadrenal paraganglia. Pheochromocytoma-paraganglioma (PPGL) syndromes are rapidly evolving entities in endocrinology and oncology. Discoveries over the last decade have significantly improved our understanding of the disease. These include the finding of new hereditary forms of PPGL and their associated susceptibility genes. Additionally, the availability of new functional imaging tools and advances in targeted radionuclide therapy have improved diagnostic accuracy and provided us with new therapeutic options. In this review article, we present the most recent advances in this field and provide an update of the biochemical classification that further reflects our understanding of the disease.

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          Most cited references93

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          Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma.

          We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.
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            HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability.

            Individuals with hemizygous germline fumarate hydratase (FH) mutations are predisposed to renal cancer. These tumors predominantly exhibit functional inactivation of the remaining wild-type allele, implicating FH inactivation as a tumor-promoting event. Hypoxia-inducible factors are expressed in many cancers and are increased in clear cell renal carcinomas. Under normoxia, the HIFs are labile due to VHL-dependent proteasomal degradation, but stabilization occurs under hypoxia due to inactivation of HIF prolyl hydroxylase (HPH), which prevents HIF hydroxylation and VHL recognition. We demonstrate that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Further, we show that fumarate acts as a competitive inhibitor of HPH. These data delineate a novel fumarate-dependent pathway for regulating HPH activity and HIF protein levels.
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              Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity.

              The neuroendocrine tumours pheochromocytomas and paragangliomas carry the highest degree of heritability in human neoplasms, enabling genetic alterations to be traced to clinical phenotypes through their transmission in families. Mutations in more than a dozen distinct susceptibility genes have implicated multiple pathways in these tumours, offering insights into kinase downstream signalling interactions and hypoxia regulation, and uncovering links between metabolism, epigenetic remodelling and cell growth. These advances extend to co-occurring tumours, including renal, thyroid and gastrointestinal malignancies. Hereditary pheochromocytomas and paragangliomas are powerful models for recognizing cancer driver events, which can be harnessed for diagnostic purposes and for guiding the future development of targeted therapies.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                27 November 2018
                2018
                : 9
                : 515
                Affiliations
                [1] 1Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD, United States
                [2] 2National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD, United States
                [3] 3Cleveland Clinic, Adrenal Center, Endocrinology and Metabolism Institute , Cleveland, OH, United States
                [4] 4Provincial Hospital , Castellon, Spain
                Author notes

                Edited by: Derek LeRoith, Icahn School of Medicine at Mount Sinai, United States

                Reviewed by: Luiz Eduardo Armondi Wildemberg, Instituto Estadual do Cérebro Paulo Niemeyer, Brazil; Agnese Barnabei, Istituto Nazionale del Cancro Regina Elena, Italy

                *Correspondence: Karel Pacak karel@ 123456mail.nih.gov

                This article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology

                †These authors share co-first authorship

                Article
                10.3389/fendo.2018.00515
                6277481
                30538672
                8e033a2b-f5b8-44e3-bae2-b774d023e034
                Copyright © 2018 Alrezk, Suarez, Tena and Pacak.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 24 April 2018
                : 16 August 2018
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 112, Pages: 13, Words: 9989
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: Z1AHD008735
                Categories
                Endocrinology
                Review

                Endocrinology & Diabetes
                pheochromocytoma,paraganglioma,genetics,biochemical classification,dotatate,prrt

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