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

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    103 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

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    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Pantaleo, M. A., Astolfi, A., Indio, V., Moore, R., Thiessen, N., Heinrich, M. C., Gnocchi, C., Santini, D., Catena, F., Formica, S., Martelli, P. L., Casadio, R., Pession, A., & Biasco, G. (2011). SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. Journal of the National Cancer Institute, 103(12), 983-987. https://doi.org/10.1093/jnci/djr130