title: Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRα genotype evaluated by next generation sequencing (NGS).
abstract: About 85% of GISTs are associated with KIT and PDGFRα gene mutations, which predict response to tyrosine kinase inhibitors. Although the outcomes in patients affected by GIST have dramatically improved, tumor progression control still remains a challenge. The aim of this study is the genomic characterization of individual metastatic KIT-exon 11-mutant GIST to identify additional aberrations and simultaneous molecular events representing potential therapeutic targets.Seven patients with metastatic GIST were studied with whole transcriptome sequencing and copy number analysis. Somatic single nucleotide variations were called; however, no shared mutated genes were detected except KIT. Almost all patients showed loss of genomic regions containing tumor suppressor genes, sometimes coupled with single nucleotide mutation of the other allele. Additionally, six fusion transcripts were found and three patients showed amplifications involving known oncogenes.Evaluating the concordance between CN status and mRNA expression levels, we detected overexpression of CCND2 and EGFR and silencing of CDKN2A, CDKN2C, SMARCB1, PTEN and DMD. Altered expression of these genes could be responsible for aberrant activation of signaling pathways that support tumor growth. In this work, we assessed the effect of Hedgehog pathway inhibition in GIST882 cells, which causes decrement of cell viability associated with reduction of KIT expression.Additional genomic alterations not previously reported in GIST were found even if not shared by all samples. This contributes to a more detailed molecular understanding of this disease, useful for identification of new targets and novel therapeutics and representing a possible point of departure for a truly individualized clinical approach.
authors.affiliation: Department of Specialized, Experimental, and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Maristella
authors.initials: M
authors.lastname: Saponara
authors.affiliation: Interdepartmental Centre of Cancer Research "G. Prodi", University of Bologna, Bologna, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Urbini
authors.affiliation: Interdepartmental Centre of Cancer Research "G. Prodi", University of Bologna, Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Astolfi
authors.affiliation: Interdepartmental Centre of Cancer Research "G. Prodi", University of Bologna, Bologna, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Indio
authors.affiliation: Department of General and Emergency Surgery and Organ Transplantation, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ercolani
authors.affiliation: Department of General and Emergency Surgery and Organ Transplantation, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Del Gaudio
authors.affiliation: Pathology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Santini
authors.affiliation: Pathology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Maria Giulia
authors.initials: MG
authors.lastname: Pirini
authors.affiliation: Laboratory of Molecular Oncologic and Transplantation Pathology, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Fiorentino
authors.affiliation: Department of Specialized, Experimental, and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Nannini
authors.affiliation: Department of Specialized, Experimental, and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Cristian
authors.initials: C
authors.lastname: Lolli
authors.affiliation: Department of Specialized, Experimental, and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Mandrioli
authors.affiliation: Department of Specialized, Experimental, and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Gatto
authors.affiliation: Department of Specialized, Experimental, and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Brandi
authors.affiliation: Department of Specialized, Experimental, and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.|Interdepartmental Centre of Cancer Research "G. Prodi", University of Bologna, Bologna, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Biasco
authors.affiliation: Department of General and Emergency Surgery and Organ Transplantation, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Antonio Daniele
authors.initials: AD
authors.lastname: Pinna
authors.affiliation: Department of Specialized, Experimental, and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.|Interdepartmental Centre of Cancer Research "G. Prodi", University of Bologna, Bologna, Italy.
authors.forename: Maria Abbondanza
authors.initials: MA
authors.lastname: Pantaleo
mesh_terms: D000368:Aged; D001483:Base Sequence; D002478:Cells, Cultured; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D056915:DNA Copy Number Variations; D005091:Exons / Q000235:genetics*; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D053823:Hedgehog Proteins / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: D053823:Hedgehog Proteins; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: CCND2; CDKN2C; DMD; GIST; NGS; PTEN