title: Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations.
abstract: Carney-Stratakis syndrome, an inherited condition predisposing affected individuals to gastrointestinal stromal tumor (GIST) and paraganglioma, is caused by germline mutations in succinate dehydrogenase (SDH) subunits B, C, or D, leading to dysfunction of complex II of the electron transport chain. We evaluated the role of defective cellular respiration in sporadic GIST lacking mutations in KIT or PDGFRA (WT). Thirty-four patients with WT GIST without a personal or family history of paraganglioma were tested for SDH germline mutations. WT GISTs lacking demonstrable SDH genetic inactivation were evaluated for SDHB expression by immunohistochemistry and Western blotting and for complex II activity. For comparison, SDHB expression was also determined in KIT mutant and neurofibromatosis-1-associated GIST, and complex II activity was also measured in SDH-deficient paraganglioma and KIT mutant GIST; 4 of 34 patients (12%) with WT GIST without a personal or family history of paraganglioma had germline mutations in SDHB or SDHC. WT GISTs lacking somatic mutations or deletions in SDH subunits had either complete loss of or substantial reduction in SDHB protein expression, whereas most KIT mutant GISTs had strong SDHB expression. Complex II activity was substantially decreased in WT GISTs. WT GISTs, particularly those in younger patients, have defects in SDH mitochondrial complex II, and in a subset of these patients, GIST seems to arise from germline-inactivating SDH mutations. Testing for germline mutations in SDH is recommended in patients with WT GIST. These findings highlight a potential central role of SDH dysregulation in WT GIST oncogenesis.
authors.affiliation: Department of Pediatric Hematology-Oncology, Dana Farber Cancer Institute and Children's Hospital, Boston, MA 02115, USA. kjaneway@partners.org
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Janeway
authors.forename: Su Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Maya
authors.initials: M
authors.lastname: Lodish
authors.forename: Vânia
authors.initials: V
authors.lastname: Nosé
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: José
authors.initials: J
authors.lastname: Gaal
authors.forename: Patricia L M
authors.initials: PL
authors.lastname: Dahia
authors.forename: Bernadette
authors.initials: B
authors.lastname: Liegl
authors.forename: Evan R
authors.initials: ER
authors.lastname: Ball
authors.forename: Margarita
authors.initials: M
authors.lastname: Raygada
authors.forename: Angela H
authors.initials: AH
authors.lastname: Lai
authors.forename: Lorna
authors.initials: L
authors.lastname: Kelly
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.forename: Maureen
authors.initials: M
authors.lastname: O'Sullivan
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Lee
authors.initials: L
authors.lastname: Helman
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000293:Adolescent; D015153:Blotting, Western; D019069:Cell Respiration / Q000235:genetics / Q000502:physiology*; D004252:DNA Mutational Analysis; D042963:Electron Transport Complex II / Q000235:genetics / Q000378:metabolism; D046152:Gastrointestinal Stromal Tumors / Q000201:enzymology*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D010235:Paraganglioma / Q000201:enzymology; D020641:Polymorphism, Single Nucleotide; D021122:Protein Subunits / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome
chemical_list: D021122:Protein Subunits; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha