SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing

Maria A. Pantaleo, Annalisa Astolfi, Valentina Indio, Richard Moore, Nina Thiessen, Michael C. Heinrich, Chiara Gnocchi, Donatella Santini, Fausto Catena, Serena Formica, Pier Luigi Martelli, Rita Casadio, Andrea Pession, Guido Biasco

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)983-987
Number of pages5
JournalJournal of the National Cancer Institute
Volume103
Issue number12
DOIs
StatePublished - Jun 22 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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