title: 15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma-paraganglioma syndromes characterized by germline SDHB and SDHD mutations.
abstract: 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.
authors.affiliation: Department of PathologyRoswell Park Cancer Institute, Buffalo, New York 14263, USADepartment of Medical GeneticsCambridge NIHR Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, UK bora.baysal@roswellpark.org.
authors.forename: Bora E
authors.initials: BE
authors.lastname: Baysal
authors.affiliation: Department of PathologyRoswell Park Cancer Institute, Buffalo, New York 14263, USADepartment of Medical GeneticsCambridge NIHR Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000818:Animals; D018095:Germ-Line Mutation; D006801:Humans; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D010235:Paraganglioma / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics*
chemical_list: C491545:SDHD protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase
keywords: molecular biology; molecular genetics; neoplasia; neuroendocrine tumors; pheochromocytoma