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Int J Mol Sci. 2018 Mar 4;19(3). pii: E732. doi: 10.3390/ijms19030732.

Integrated Molecular Characterization of Gastrointestinal Stromal Tumors (GIST) Harboring the Rare D842V Mutation in PDGFRA Gene.

Author information

1
"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna 40138 Italy. valentina.indio2@unibo.it.
2
"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna 40138 Italy. annalisa.astolfi@unibo.it.
3
"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna 40138 Italy. giuseppe.tarantino6@unibo.it.
4
"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna 40138 Italy. milena.urbini2@unibo.it.
5
Division of Hematology and Oncology, Portland VA Health Care System and OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA. patterja@ohsu.edu.
6
Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy. margherita.nannini@unibo.it.
7
Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy. maristella.saponara@unibo.it.
8
Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy. lidia.gatto83@gmail.com.
9
Pathology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy. donatella.santini@aosp.bo.it.
10
Department of Physics and Astronomy, L. Galvani Center for Biocomplexity, Biophysics and Systems Biology, University of Bologna, Bologna 40138, Italy.
11
Department of Physics and Astronomy, L. Galvani Center for Biocomplexity, Biophysics and Systems Biology, University of Bologna, Bologna 40138, Italy. gastone.castellani@unibo.it.
12
Department of Physics and Astronomy, L. Galvani Center for Biocomplexity, Biophysics and Systems Biology, University of Bologna, Bologna 40138, Italy. daniel.remondini@unibo.it.
13
Laboratory of Oncological and Transplant Molecular Pathology-Pathology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy. michelangelo.fiorentino@aosp.bo.it.
14
Department of Hematology and Medical Oncology, Fox Chase Cancer Center, Temple University Philadelphia, PA 19111, USA. margaret.vonmehren@fccc.edu.
15
Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy. giovanni.brandi@unibo.it.
16
"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna 40138 Italy. guido.biasco@unibo.it.
17
Division of Hematology and Oncology, Portland VA Health Care System and OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA. guido.biasco@unibo.it.
18
Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy. guido.biasco@unibo.it.
19
Division of Hematology and Oncology, Portland VA Health Care System and OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA. heinrich@ohsu.edu.
20
"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna 40138 Italy. maria.pantaleo@unibo.it.
21
Division of Hematology and Oncology, Portland VA Health Care System and OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA. maria.pantaleo@unibo.it.
22
Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy. maria.pantaleo@unibo.it.

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.

KEYWORDS:

D842V; GIST; KIT; PDGFRA; crenolanib; gastrointestinal stromal tumors

PMID:
29510530
PMCID:
PMC5877593
DOI:
10.3390/ijms19030732
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Maria A. Pantaleo declares research grant support by Novartis. The other authors declare no conflict of interest

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