title: Genetic mutation screening in an italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients.
abstract: To assess the prevalence of genetic mutations in nonsyndromic pheochromocytoma/paraganglioma (PHEO/PGL) patients we have performed a systematic search for mutations in the succinate dehydrogenase (SDH) B, C, and D subunits, von Hippel-Lindau (VHL), and RET genes by direct bidirectional sequencing. Patients were selected from the medical records of hypertension centers. After exclusion of syndromic patients, 45 patients with familial (F+, n=3) and sporadic (F-, n=42) cases of isolated PHEO/PGL were considered. They included 35 patients with PHEO, 7 with PGL, and 3 with head/neck PGL (hnPGL). Three patients with PHEO (2F-, 1F+) presented VHL mutations (P86A, G93C, and R167W), six with PGL (4F-, 2F+) were positive for SDH or VHL mutations (SDHB R230G in two patients, SDHB S8F, R46Q, R90Q, and VHL P81L in one subject each), and one with hnPGL carried the SDHD 348-351delGACT mutation. We have also detected missense (SDHB S163P, SDHD H50R and G12S), synonymous (SDHB A6A, SDHD S68S), and intronic mutations that have been considered nonpathological polymorphic variants. No mutation was found in SDHC or RET genes. Our data indicate that germline mutations of VHL and SDH subunits are not infrequent in familial as well as in sporadic cases of nonsyndromic PHEO/PGL (overall, 12 of 45 probands, 22%). Accordingly, screening for such mutations seems to be justified. However, a more precise characterization of the functional relevance of any observed sequence variant and of other genetic and environmental determinants of neoplastic transformation is essential in order to plan appropriate protocols for family screening and follow-up.
authors.affiliation: Department of Internal Medicine, Laboratory of Molecular Medicine, University of Brescia, Italy. castella@med.unibs.it
authors.forename: M
authors.initials: M
authors.lastname: Castellano
authors.forename: L
authors.initials: L
authors.lastname: Mori
authors.forename: M
authors.initials: M
authors.lastname: Giacchè
authors.forename: E
authors.initials: E
authors.lastname: Agliozzo
authors.forename: R
authors.initials: R
authors.lastname: Tosini
authors.forename: A
authors.initials: A
authors.lastname: Panarotto
authors.forename: C
authors.initials: C
authors.lastname: Cappelli
authors.forename: P
authors.initials: P
authors.lastname: Mulatero
authors.forename: D
authors.initials: D
authors.lastname: Cumetti
authors.forename: F
authors.initials: F
authors.lastname: Veglio
authors.forename: E
authors.initials: E
authors.lastname: Agabiti-Rosei
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D015331:Cohort Studies; D017931:DNA Primers; D006801:Humans; D007558:Italy; D008969:Molecular Sequence Data; D009154:Mutation; D010235:Paraganglioma / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013385:Succinate Dehydrogenase / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
chemical_list: D017931:DNA Primers; D013385:Succinate Dehydrogenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C497446:VHL protein, human