title: SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing.
abstract: Approximately 10%-15% of gastrointestinal stromal tumors (GISTs) in adults do not harbor any mutation in the KIT or PDGFRA genes (ie, KIT/PDGFRA wild-type GISTs). Recently, mutations in SDHB and SDHC (which encode succinate dehydrogenase subunits B and C, respectively) but not in SDHA and SDHD (which encode subunits A and D, respectively) were identified in KIT/PDGFRA wild-type GISTs. To search for novel pathogenic mutations, we sequenced the tumor transcriptome of two young adult patients who developed sporadic KIT/PDGFRA wild-type GISTs by using a massively parallel sequencing approach. The only variants identified as disease related by computational analysis were in SDHA. One patient carried the homozygous nonsense mutation p.Ser384X, the other patient was a compound heterozygote harboring a p.Arg31X nonsense mutation and a p.Arg589Trp missense mutation. The heterozygous nonsense mutations in both patients were present in germline DNA isolated from peripheral blood. Protein structure analysis indicates that all three mutations lead to functional inactivation of the protein. This is the first report, to our knowle dge, that identifies SDHA inactivation as a common oncogenic event in GISTs that lack a mutation in KIT and PDGFRA.
authors.affiliation: Department of Hematology and Oncological Sciences "L.A.Seragnoli," Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy. maria.pantaleo@unibo.it.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pantaleo
authors.forename: Annalisa
authors.initials: A
authors.lastname: Astolfi
authors.forename: Valentina
authors.initials: V
authors.lastname: Indio
authors.forename: Richard
authors.initials: R
authors.lastname: Moore
authors.forename: Nina
authors.initials: N
authors.lastname: Thiessen
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: Chiara
authors.initials: C
authors.lastname: Gnocchi
authors.forename: Donatella
authors.initials: D
authors.lastname: Santini
authors.forename: Fausto
authors.initials: F
authors.lastname: Catena
authors.forename: Serena
authors.initials: S
authors.lastname: Formica
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Martelli
authors.forename: Rita
authors.initials: R
authors.lastname: Casadio
authors.forename: Andrea
authors.initials: A
authors.lastname: Pession
authors.forename: Guido
authors.initials: G
authors.lastname: Biasco
mesh_terms: D042963:Electron Transport Complex II / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D018401:Sample Size; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D055815:Young Adult
chemical_list: D042963:Electron Transport Complex II; C511268:SDHA protein, human; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha