title: Candidate gene mutation analysis in bilateral adrenal pheochromocytoma and sympathetic paraganglioma.
abstract: Pheochromocytomas (PCCs) are rare tumors that arise from chromaffin tissue in the adrenal medulla, but can also occur in the abdomen outside the adrenals and are then called sympathetic paragangliomas (sPGLs). According to the literature, between 15 and 25% of apparently sporadic adrenal PCC and sPGL are caused by germline mutations in RET, von Hippel-Lindau disease (VHL), succinate dehydrogenase subunit B (SDHB), or subunit D SDHD. However, few studies have addressed the mutationfrequency of these candidate genes in selected subgroups of PCC andsPGL, such as bilateral adrenal PCC or extra-adrenal sPGL, and none have looked at somatic mutations by analyzing tumor tissue. Therefore, we have investigated the occurrence of germline and somatic mutations in RET, VHL, SDHB, and SDHD in comparatively large series of bilateral adrenal PCC (n = 33 patients) and sPGL (n = 26 patients), with the aim of determining the mutation frequency of each of these genes and to establish a genetic testing algorithm. Twenty-one RET, two VHL germline, and one SDHD mutations were found in the patients with bilateral adrenal PCC. In sPGL, one novel SDHB germline and one novel SDHB somatic mutation were observed. In addition, two SDHD germline mutations were found. We conclude that germline RET mutations are predominantly found in bilateral PCC, and that somatic and germline SDHB and SDHD mutations usually occur in sPGL, which has practical consequences for genetic testing algorithms. We suggest that sequential mutation analysis should be directed first at RET, followed by VHL and SDHD for patients with bilateral adrenal PCC at diagnosis, and at SDHB and SDHD for patients with sPGL.
authors.affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus MC, University Medical Center Rotterdam, JNI room 222, PO Box 2040, 3000 CR Rotterdam, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Korpershoek
authors.forename: Bart-Jeroen
authors.initials: BJ
authors.lastname: Petri
authors.forename: Francien H
authors.initials: FH
authors.lastname: van Nederveen
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
authors.forename: Albert A
authors.initials: AA
authors.lastname: Verhofstad
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.forename: Sonja
authors.initials: S
authors.lastname: Schmid
authors.forename: Aurel
authors.initials: A
authors.lastname: Perren
authors.forename: Paul
authors.initials: P
authors.lastname: Komminoth
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D004252:DNA Mutational Analysis; D005260:Female; D052138:Genes, Neoplasm; D018095:Germ-Line Mutation; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010235:Paraganglioma / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D051381:Rats; D013385:Succinate Dehydrogenase / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
chemical_list: D007506:Iron-Sulfur Proteins; C491545:SDHD protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C497446:VHL protein, human