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 Heinrich, Chiara Gnocchi, Donatella Santini, Fausto Catena, Serena Formica, Pier Luigi Martelli, Rita Casadio, Andrea Pession, Guido Biasco

    Research output: Contribution to journalArticle

    102 Citations (Scopus)

    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

    Fingerprint

    High-Throughput Nucleotide Sequencing
    Gastrointestinal Stromal Tumors
    Nonsense Codon
    Mutation
    Succinate Dehydrogenase
    Missense Mutation
    Heterozygote
    Transcriptome
    Young Adult
    Proteins
    DNA
    Genes
    Neoplasms

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. / Pantaleo, Maria A.; Astolfi, Annalisa; Indio, Valentina; Moore, Richard; Thiessen, Nina; Heinrich, Michael; Gnocchi, Chiara; Santini, Donatella; Catena, Fausto; Formica, Serena; Martelli, Pier Luigi; Casadio, Rita; Pession, Andrea; Biasco, Guido.

    In: Journal of the National Cancer Institute, Vol. 103, No. 12, 22.06.2011, p. 983-987.

    Research output: Contribution to journalArticle

    Pantaleo, MA, Astolfi, A, Indio, V, Moore, R, Thiessen, N, Heinrich, M, Gnocchi, C, Santini, D, Catena, F, Formica, S, Martelli, PL, 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, vol. 103, no. 12, pp. 983-987. https://doi.org/10.1093/jnci/djr130
    Pantaleo, Maria A. ; Astolfi, Annalisa ; Indio, Valentina ; Moore, Richard ; Thiessen, Nina ; Heinrich, Michael ; Gnocchi, Chiara ; Santini, Donatella ; Catena, Fausto ; Formica, Serena ; Martelli, Pier Luigi ; Casadio, Rita ; Pession, Andrea ; Biasco, Guido. / SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. In: Journal of the National Cancer Institute. 2011 ; Vol. 103, No. 12. pp. 983-987.
    @article{cfcdfbb7b36d4ec6b2ad0b73af6f8780,
    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.",
    author = "Pantaleo, {Maria A.} and Annalisa Astolfi and Valentina Indio and Richard Moore and Nina Thiessen and Michael Heinrich and Chiara Gnocchi and Donatella Santini and Fausto Catena and Serena Formica and Martelli, {Pier Luigi} and Rita Casadio and Andrea Pession and Guido Biasco",
    year = "2011",
    month = "6",
    day = "22",
    doi = "10.1093/jnci/djr130",
    language = "English (US)",
    volume = "103",
    pages = "983--987",
    journal = "Journal of the National Cancer Institute",
    issn = "0027-8874",
    publisher = "Oxford University Press",
    number = "12",

    }

    TY - JOUR

    T1 - SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing

    AU - Pantaleo, Maria A.

    AU - Astolfi, Annalisa

    AU - Indio, Valentina

    AU - Moore, Richard

    AU - Thiessen, Nina

    AU - Heinrich, Michael

    AU - Gnocchi, Chiara

    AU - Santini, Donatella

    AU - Catena, Fausto

    AU - Formica, Serena

    AU - Martelli, Pier Luigi

    AU - Casadio, Rita

    AU - Pession, Andrea

    AU - Biasco, Guido

    PY - 2011/6/22

    Y1 - 2011/6/22

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=79959715470&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=79959715470&partnerID=8YFLogxK

    U2 - 10.1093/jnci/djr130

    DO - 10.1093/jnci/djr130

    M3 - Article

    VL - 103

    SP - 983

    EP - 987

    JO - Journal of the National Cancer Institute

    JF - Journal of the National Cancer Institute

    SN - 0027-8874

    IS - 12

    ER -