title: Epigenetic Mutation of the Succinate Dehydrogenase C Promoter in a Patient With Two Paragangliomas.
abstract: BACKGROUND
  Mutational inactivation of the succinate dehydrogenase (SDH) complex is a well-described cause of tumor development in pheochromocytomas/paragangliomas (PPGLs) and gastrointestinal stromal tumors (GISTs). Epigenetic inactivation of the SDHC gene is a more recently discovered phenomenon, which so far has only been described in GISTs and PPGLs from patients with Carney triad syndrome.
  
  
  METHODS
  A 33-year-old patient presented with two abdominal paragangliomas (PGLs) and an adrenocortical adenoma. Both PGLs showed high succinate:fumarate ratios indicative of SDHx mutations; however, no mutations in any of the known PPGL susceptibility genes were found in leucocyte or tumor DNA. We identified methylation of the SDHC promoter region in both PGLs, which coincided with decreased SDHC expression at mRNA and protein levels and a hypermethylated epigenomic signature (CpG island methylator phenotype). Low-level SDHC promoter methylation was also observed in the adenoma but not in normal adrenal tissue or blood, suggesting postzygotic somatic mosaicism for SDHC promoter methylation in the patient.
  
  
  CONCLUSIONS
  This report provides evidence that SDHC promoter methylation can cause PGLs due to SDHC inactivation, emphasizing the importance of considering epigenetic changes and functional readouts in the genetic evaluation of patients not only with GISTs and Carney triad but also with PPGL.
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine (S.R., B.N., A.M., M.Men., G.E.) and Institute for Pathology (M.Mei.), University Hospital Carl Gustav Carus, and Institute for Clinical Genetics (B.K.), Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.R., M.Ma.), University of Florence and Istituto Toscano Tumori, 50139 Florence, Italy; Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, and Centro de Investigación Biomédica en Red de Enfermedades Raras (A.A.d.C., M.R.), 28029 Madrid, Spain; and Department of Medicine III (C.S., G.E.), University Hospital Dresden, 01307 Dresden, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Richter
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine (S.R., B.N., A.M., M.Men., G.E.) and Institute for Pathology (M.Mei.), University Hospital Carl Gustav Carus, and Institute for Clinical Genetics (B.K.), Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.R., M.Ma.), University of Florence and Istituto Toscano Tumori, 50139 Florence, Italy; Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, and Centro de Investigación Biomédica en Red de Enfermedades Raras (A.A.d.C., M.R.), 28029 Madrid, Spain; and Department of Medicine III (C.S., G.E.), University Hospital Dresden, 01307 Dresden, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Klink
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine (S.R., B.N., A.M., M.Men., G.E.) and Institute for Pathology (M.Mei.), University Hospital Carl Gustav Carus, and Institute for Clinical Genetics (B.K.), Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.R., M.Ma.), University of Florence and Istituto Toscano Tumori, 50139 Florence, Italy; Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, and Centro de Investigación Biomédica en Red de Enfermedades Raras (A.A.d.C., M.R.), 28029 Madrid, Spain; and Department of Medicine III (C.S., G.E.), University Hospital Dresden, 01307 Dresden, Germany.
authors.forename: Brit
authors.initials: B
authors.lastname: Nacke
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine (S.R., B.N., A.M., M.Men., G.E.) and Institute for Pathology (M.Mei.), University Hospital Carl Gustav Carus, and Institute for Clinical Genetics (B.K.), Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.R., M.Ma.), University of Florence and Istituto Toscano Tumori, 50139 Florence, Italy; Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, and Centro de Investigación Biomédica en Red de Enfermedades Raras (A.A.d.C., M.R.), 28029 Madrid, Spain; and Department of Medicine III (C.S., G.E.), University Hospital Dresden, 01307 Dresden, Germany.
authors.forename: Aguirre A
authors.initials: AA
authors.lastname: de Cubas
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine (S.R., B.N., A.M., M.Men., G.E.) and Institute for Pathology (M.Mei.), University Hospital Carl Gustav Carus, and Institute for Clinical Genetics (B.K.), Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.R., M.Ma.), University of Florence and Istituto Toscano Tumori, 50139 Florence, Italy; Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, and Centro de Investigación Biomédica en Red de Enfermedades Raras (A.A.d.C., M.R.), 28029 Madrid, Spain; and Department of Medicine III (C.S., G.E.), University Hospital Dresden, 01307 Dresden, Germany.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Mangelis
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine (S.R., B.N., A.M., M.Men., G.E.) and Institute for Pathology (M.Mei.), University Hospital Carl Gustav Carus, and Institute for Clinical Genetics (B.K.), Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.R., M.Ma.), University of Florence and Istituto Toscano Tumori, 50139 Florence, Italy; Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, and Centro de Investigación Biomédica en Red de Enfermedades Raras (A.A.d.C., M.R.), 28029 Madrid, Spain; and Department of Medicine III (C.S., G.E.), University Hospital Dresden, 01307 Dresden, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Rapizzi
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine (S.R., B.N., A.M., M.Men., G.E.) and Institute for Pathology (M.Mei.), University Hospital Carl Gustav Carus, and Institute for Clinical Genetics (B.K.), Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.R., M.Ma.), University of Florence and Istituto Toscano Tumori, 50139 Florence, Italy; Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, and Centro de Investigación Biomédica en Red de Enfermedades Raras (A.A.d.C., M.R.), 28029 Madrid, Spain; and Department of Medicine III (C.S., G.E.), University Hospital Dresden, 01307 Dresden, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Meinhardt
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine (S.R., B.N., A.M., M.Men., G.E.) and Institute for Pathology (M.Mei.), University Hospital Carl Gustav Carus, and Institute for Clinical Genetics (B.K.), Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.R., M.Ma.), University of Florence and Istituto Toscano Tumori, 50139 Florence, Italy; Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, and Centro de Investigación Biomédica en Red de Enfermedades Raras (A.A.d.C., M.R.), 28029 Madrid, Spain; and Department of Medicine III (C.S., G.E.), University Hospital Dresden, 01307 Dresden, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Skondra
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine (S.R., B.N., A.M., M.Men., G.E.) and Institute for Pathology (M.Mei.), University Hospital Carl Gustav Carus, and Institute for Clinical Genetics (B.K.), Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.R., M.Ma.), University of Florence and Istituto Toscano Tumori, 50139 Florence, Italy; Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, and Centro de Investigación Biomédica en Red de Enfermedades Raras (A.A.d.C., M.R.), 28029 Madrid, Spain; and Department of Medicine III (C.S., G.E.), University Hospital Dresden, 01307 Dresden, Germany.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mannelli
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine (S.R., B.N., A.M., M.Men., G.E.) and Institute for Pathology (M.Mei.), University Hospital Carl Gustav Carus, and Institute for Clinical Genetics (B.K.), Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.R., M.Ma.), University of Florence and Istituto Toscano Tumori, 50139 Florence, Italy; Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, and Centro de Investigación Biomédica en Red de Enfermedades Raras (A.A.d.C., M.R.), 28029 Madrid, Spain; and Department of Medicine III (C.S., G.E.), University Hospital Dresden, 01307 Dresden, Germany.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine (S.R., B.N., A.M., M.Men., G.E.) and Institute for Pathology (M.Mei.), University Hospital Carl Gustav Carus, and Institute for Clinical Genetics (B.K.), Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.R., M.Ma.), University of Florence and Istituto Toscano Tumori, 50139 Florence, Italy; Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, and Centro de Investigación Biomédica en Red de Enfermedades Raras (A.A.d.C., M.R.), 28029 Madrid, Spain; and Department of Medicine III (C.S., G.E.), University Hospital Dresden, 01307 Dresden, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Menschikowski
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine (S.R., B.N., A.M., M.Men., G.E.) and Institute for Pathology (M.Mei.), University Hospital Carl Gustav Carus, and Institute for Clinical Genetics (B.K.), Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; Department of Experimental and Clinical Biomedical Sciences "Mario Serio" (E.R., M.Ma.), University of Florence and Istituto Toscano Tumori, 50139 Florence, Italy; Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncológicas, and Centro de Investigación Biomédica en Red de Enfermedades Raras (A.A.d.C., M.R.), 28029 Madrid, Spain; and Department of Medicine III (C.S., G.E.), University Hospital Dresden, 01307 Dresden, Germany.
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D056733:Carney Complex / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010235:Paraganglioma / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C108096:SDHC protein, human