title: Analysis of all subunits, SDHA, SDHB, SDHC, SDHD, of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST.
abstract: Mutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. In this study, we simultaneously sequenced the genome of all subunits, SDHA, SDHB, SDHC, and SDHD in a larger series of KIT/PDGFRA wild-type GIST in order to evaluate the frequency of the mutations and explore their biological role. SDHA, SDHB, SDHC, and SDHD were sequenced on the available samples obtained from 34 KIT/PDGFRA wild-type GISTs. Of these, in 10 cases, both tumor and peripheral blood (PB) were available, in 19 cases only tumor, and in 5 cases only PB. Overall, 9 of the 34 patients with KIT/PDGFRA wild-type GIST carried mutations in one of the four subunits of the SDH complex (six patients in SDHA, two in SDHB, one in SDHC). WB and immunohistochemistry analysis showed that patients with KIT/PDGFRA wild-type GIST who harbored SDHA mutations exhibited a significant downregulation of both SDHA and SDHB protein expression, with respect to the other GIST lacking SDH mutations and to KIT/PDGFRA-mutated GIST. Clinically, four out of six patients with SDHA mutations presented with metastatic disease at diagnosis with a very slow, indolent course. Patients with KIT/PDGFRA wild-type GIST may harbor germline and/or de novo mutations of SDH complex with prevalence for mutations within SDHA, which is associated with a downregulation of SDHA and SDHB protein expression. The presence of germline mutations may suggest that these patients should be followed up for the risk of development of other cancers.
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pantaleo
authors.affiliation: 8216;Giorgio Prodi' Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Astolfi
authors.affiliation: 8216;Giorgio Prodi' Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Urbini
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Nannini
authors.affiliation: 8216;Giorgio Prodi' Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Paterini
authors.affiliation: 8216;Giorgio Prodi' Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Indio
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Maristella
authors.initials: M
authors.lastname: Saponara
authors.affiliation: 8216;Giorgio Prodi' Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Formica
authors.affiliation: Pathology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceccarelli
authors.affiliation: Biocomputing Group, Department of Biology, University of Bologna, Bologna, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Casadio
authors.affiliation: Section of Pathologic Anatomy and Division of Oncology, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Rossi
authors.affiliation: Section of Pathologic Anatomy and Division of Oncology, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Bertolini
authors.affiliation: Pathology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Santini
authors.affiliation: Pathology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Pirini
authors.affiliation: Laboratorio di Patologia Molecolare Oncologica e dei Trapianti-Pathology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Fiorentino
authors.affiliation: Oncologia Medica 1, Istituto Oncologico Veneto IOV I.R.C.C.S., Padova, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Basso
authors.affiliation: 1] Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy [2] 'Giorgio Prodi' Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Biasco
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D042963:Electron Transport Complex II / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D056726:Genetic Association Studies; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C108096:SDHC protein, human; C491545:SDHD protein, human; D042963:Electron Transport Complex II; C511268:SDHA protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha