Integrated molecular characterization of gastrointestinal stromal tumors (GIST) harboring the rare D842V mutation in PDGFRA gene

Valentina Indio, Annalisa Astolfi, Giuseppe Tarantino, Milena Urbini, Janice Patterson, Margherita Nannini, Maristella Saponara, Lidia Gatto, Donatella Santini, Italo F. Do Valle, Gastone Castellani, Daniel Remondini, Michelangelo Fiorentino, Margaret Von Mehren, Giovanni Brandi, Guido Biasco, Michael Heinrich, Maria Aabbondanza Pantaleo

    Research output: Contribution to journalArticle

    4 Citations (Scopus)

    Abstract

    Gastrointestinal stromal tumors (GIST) carrying the D842V activating mutation in the platelet-derived growth factor receptor alpha (PDGFRA) gene are a very rare subgroup of GIST (about 10%) known to be resistant to conventional tyrosine kinase inhibitors (TKIs) and to show an indolent behavior. In this study, we performed an integrated molecular characterization of D842V mutant GIST by whole-transcriptome and whole-exome sequencing coupled with protein–ligand interaction modelling to identify the molecular signature and any additional recurrent genomic event related to their clinical course. We found a very specific gene expression profile of D842V mutant tumors showing the activation of G-protein-coupled receptor (GPCR) signaling and a relative downregulation of cell cycle processes. Beyond D842V, no recurrently mutated genes were found in our cohort. Nevertheless, many private, clinically relevant alterations were found in each tumor (TP53, IDH1, FBXW7, SDH-complex). Molecular modeling of PDGFRA D842V suggests that the mutant protein binds imatinib with lower affinity with respect to wild-type structure, showing higher stability during the interaction with other type I TKIs (like crenolanib). D842V mutant GIST do not show any actionable recurrent molecular events of therapeutic significance, therefore this study supports the rationale of novel TKIs development that are currently being evaluated in clinical studies for the treatment of D842V mutant GIST.

    Original languageEnglish (US)
    Article number732
    JournalInternational Journal of Molecular Sciences
    Volume19
    Issue number3
    DOIs
    StatePublished - Mar 4 2018

    Fingerprint

    Platelet-Derived Growth Factor alpha Receptor
    Gastrointestinal Stromal Tumors
    mutations
    Platelets
    platelets
    genes
    Tumors
    tumors
    Genes
    Mutation
    Protein-Tyrosine Kinases
    tyrosine
    inhibitors
    Transcriptome
    Exome
    Mutant Proteins
    G-Protein-Coupled Receptors
    proteins
    Proteins
    Molecular modeling

    Keywords

    • Crenolanib
    • D842V
    • Gastrointestinal stromal tumors
    • GIST
    • KIT
    • PDGFRA

    ASJC Scopus subject areas

    • Catalysis
    • Molecular Biology
    • Spectroscopy
    • Computer Science Applications
    • Physical and Theoretical Chemistry
    • Organic Chemistry
    • Inorganic Chemistry

    Cite this

    Integrated molecular characterization of gastrointestinal stromal tumors (GIST) harboring the rare D842V mutation in PDGFRA gene. / Indio, Valentina; Astolfi, Annalisa; Tarantino, Giuseppe; Urbini, Milena; Patterson, Janice; Nannini, Margherita; Saponara, Maristella; Gatto, Lidia; Santini, Donatella; Do Valle, Italo F.; Castellani, Gastone; Remondini, Daniel; Fiorentino, Michelangelo; Von Mehren, Margaret; Brandi, Giovanni; Biasco, Guido; Heinrich, Michael; Pantaleo, Maria Aabbondanza.

    In: International Journal of Molecular Sciences, Vol. 19, No. 3, 732, 04.03.2018.

    Research output: Contribution to journalArticle

    Indio, V, Astolfi, A, Tarantino, G, Urbini, M, Patterson, J, Nannini, M, Saponara, M, Gatto, L, Santini, D, Do Valle, IF, Castellani, G, Remondini, D, Fiorentino, M, Von Mehren, M, Brandi, G, Biasco, G, Heinrich, M & Pantaleo, MA 2018, 'Integrated molecular characterization of gastrointestinal stromal tumors (GIST) harboring the rare D842V mutation in PDGFRA gene', International Journal of Molecular Sciences, vol. 19, no. 3, 732. https://doi.org/10.3390/ijms19030732
    Indio, Valentina ; Astolfi, Annalisa ; Tarantino, Giuseppe ; Urbini, Milena ; Patterson, Janice ; Nannini, Margherita ; Saponara, Maristella ; Gatto, Lidia ; Santini, Donatella ; Do Valle, Italo F. ; Castellani, Gastone ; Remondini, Daniel ; Fiorentino, Michelangelo ; Von Mehren, Margaret ; Brandi, Giovanni ; Biasco, Guido ; Heinrich, Michael ; Pantaleo, Maria Aabbondanza. / Integrated molecular characterization of gastrointestinal stromal tumors (GIST) harboring the rare D842V mutation in PDGFRA gene. In: International Journal of Molecular Sciences. 2018 ; Vol. 19, No. 3.
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    abstract = "Gastrointestinal stromal tumors (GIST) carrying the D842V activating mutation in the platelet-derived growth factor receptor alpha (PDGFRA) gene are a very rare subgroup of GIST (about 10{\%}) known to be resistant to conventional tyrosine kinase inhibitors (TKIs) and to show an indolent behavior. In this study, we performed an integrated molecular characterization of D842V mutant GIST by whole-transcriptome and whole-exome sequencing coupled with protein–ligand interaction modelling to identify the molecular signature and any additional recurrent genomic event related to their clinical course. We found a very specific gene expression profile of D842V mutant tumors showing the activation of G-protein-coupled receptor (GPCR) signaling and a relative downregulation of cell cycle processes. Beyond D842V, no recurrently mutated genes were found in our cohort. Nevertheless, many private, clinically relevant alterations were found in each tumor (TP53, IDH1, FBXW7, SDH-complex). Molecular modeling of PDGFRA D842V suggests that the mutant protein binds imatinib with lower affinity with respect to wild-type structure, showing higher stability during the interaction with other type I TKIs (like crenolanib). D842V mutant GIST do not show any actionable recurrent molecular events of therapeutic significance, therefore this study supports the rationale of novel TKIs development that are currently being evaluated in clinical studies for the treatment of D842V mutant GIST.",
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    AU - Indio, Valentina

    AU - Astolfi, Annalisa

    AU - Tarantino, Giuseppe

    AU - Urbini, Milena

    AU - Patterson, Janice

    AU - Nannini, Margherita

    AU - Saponara, Maristella

    AU - Gatto, Lidia

    AU - Santini, Donatella

    AU - Do Valle, Italo F.

    AU - Castellani, Gastone

    AU - Remondini, Daniel

    AU - Fiorentino, Michelangelo

    AU - Von Mehren, Margaret

    AU - Brandi, Giovanni

    AU - Biasco, Guido

    AU - Heinrich, Michael

    AU - Pantaleo, Maria Aabbondanza

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