title: Implications of SDHB genetic testing in patients with sporadic pheochromocytoma.
abstract: OBJECTIVE
  Succinate dehydrogenase B (SDHB) associated pheochromocytomas (PHEOs) are associated with a higher risk of tumor aggressiveness and malignancy. The aim of the present study was to evaluate (1) the frequency of germline SDHB mutations in apparently sporadic patients with PHEO who undergo preoperative genetic testing and (2) the ability to predict pathogenic mutations.
  
  
  METHODS
  From 2012 to 2016, 82 patients underwent a PHEO surgical resection. Sixteen were operated in the context of hereditary PHEO and were excluded from analysis. Among the 66 remaining cases, 48 were preoperatively screened for an SDHB mutation. In addition to imaging studies with specific radiopharmaceuticals (123I-MIBG or18F-FDOPA) for exclusion of multifocality/metastases, 36 patients underwent18F-FDG PET/CT.
  
  
  RESULTS
  From the 48 genetically screened patients, genetic testing found a germline SDHB variant in two (4.2%) cases: a variant of unknown significance, exon 1, c.14T>G (p.Val5Gly), and a most likely pathogenic mutation, exon 5, c.440A>G (p.Tyr147Cys), according to in silico analysis. Structural and functional analyses of the protein predicted that p.Tyr147Cys mutant was pathogenic. Both tumors exhibited moderate18F-FDG PET uptake with similar uptake patterns to non-SDHB mutated PHEOs. The two patients underwent total laparoscopic adrenalectomies. Of the remaining patients, 44 underwent a laparoscopic adrenalectomy, and two had an open approach. Pathological analysis of the tumors from patients bearing two germline SDHB variants revealed a typical PHEO (PASS 0 and 2). Ex-vivo analyses (metabolomics, SDHB immunohistochemistry, loss of heterozygosity analysis) allowed a reclassification of the two SDHB variants as probably non-pathogenic variants.
  
  
  CONCLUSIONS
  This study illustrates that SDHx mutational analysis can be misleading, even if structural and functional analyses are done. Surgeons should be aware of the difficulty of classifying new SDHB variants prior to implementing SDHB mutation status into a tailored surgical management strategy of a patient.
authors.affiliation: Department of Endocrine Surgery, Conception Hospital, APHM, Aix Marseille Univ, Marseille, France.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Maignan
authors.affiliation: Department of Endocrine Surgery, Conception Hospital, APHM, Aix Marseille Univ, Marseille, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Guerin
authors.affiliation: Department of Endocrine Surgery, Conception Hospital, APHM, Aix Marseille Univ, Marseille, France.
authors.forename: Valentin
authors.initials: V
authors.lastname: Julliard
authors.affiliation: Department of Endocrine Surgery, Conception Hospital, APHM, Aix Marseille Univ, Marseille, France.
authors.forename: Nunzia-Cinzia
authors.initials: NC
authors.lastname: Paladino
authors.affiliation: Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, and University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Edward
authors.initials: E
authors.lastname: Kim
authors.affiliation: Integrative Structural & Chemical Biology (iSCB) & INT-3D Molecular Modeling Platform, Cancer Research Centre of Marseille, CNRS UMR7258, Aix Marseille Univ, Marseille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Roche
authors.affiliation: Department of Endocrinology, Conception Hospital, APHM, Aix Marseille Univ, Marseille, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Castinetti
authors.affiliation: Department of Neuropathology, La Timone University Hospital, APHM, Aix Marseille Univ, Marseille, France.
authors.forename: Wassim
authors.initials: W
authors.lastname: Essamet
authors.affiliation: UMR_S912, IRD, Aix Marseille Univ, Marseille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Mancini
authors.affiliation: ICube, UMR 7357 University of Strasbourg/CNRS and FMTS, Faculty of Medicine, Strasbourg, France.
authors.forename: Alessio
authors.initials: A
authors.lastname: Imperiale
authors.affiliation: Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, and University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Roderick
authors.initials: R
authors.lastname: Clifton-Bligh
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Conception Hospital, APHM, Aix Marseille Univ, Marseille, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Romanet
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, Conception Hospital, APHM, Aix Marseille Univ, Marseille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Barlier
authors.affiliation: Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.affiliation: Department of Endocrine Surgery, Conception Hospital, APHM, Aix Marseille Univ, Marseille, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Sebag
authors.affiliation: Department of Nuclear Medicine, La Timone University Hospital, APHM, CERIMED, Aix Marseille Univ, Marseille, France. david.taieb@ap-hm.fr.
authors.forename: David
authors.initials: D
authors.lastname: Taïeb
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000601:surgery*; D000315:Adrenalectomy / Q000379:methods*; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D004252:DNA Mutational Analysis; D005260:Female; D019788:Fluorodeoxyglucose F18; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D010535:Laparoscopy / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D010673:Pheochromocytoma / Q000000981:diagnostic imaging / Q000235:genetics* / Q000601:surgery*; D000072078:Positron Emission Tomography Computed Tomography; D019275:Radiopharmaceuticals; D013385:Succinate Dehydrogenase / Q000235:genetics*
chemical_list: D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase
keywords: Pheochromocytomas; Radionuclide imaging; SDHB