title: Genome-Wide Analysis Identifies MEN1 and MAX Mutations and a Neuroendocrine-Like Molecular Heterogeneity in Quadruple WT GIST.
abstract: Quadruple wild-type (WT) gastrointestinal stromal tumor (GIST) is a genomic subgroup lacking KIT/PDGFRA/RAS pathway mutations, with an intact succinate dehydrogenase (SDH) complex. The aim of this work is to perform a wide comprehensive genomic study on quadruple WT GIST to improve the characterization of these patients. We selected 14 clinical cases of quadruple WT GIST, of which nine cases showed sufficient DNA quality for whole exome sequencing (WES). NF1 alterations were identified directly by WES. Gene expression from whole transcriptome sequencing (WTS) and miRNA profiling were performed using fresh-frozen, quadruple WT GIST tissue specimens and compared with SDH and KIT/PDGFRA-mutant GIST. WES identified an average of 18 somatic mutations per sample. The most relevant somatic oncogenic mutations identified were in TP53, MEN1, MAX, FGF1R, CHD4, and CTDNN2. No somatic alterations in NF1 were identified in the analyzed cohort. A total of 247 mRNA transcripts and 66 miRNAs were differentially expressed specifically in quadruple WT GIST. Overexpression of specific molecular markers (COL22A1 and CALCRL) and genes involved in neural and neuroendocrine lineage (ASCL1, Family B GPCRs) were detected and further supported by predicted miRNA target analysis. Quadruple WT GIST show a specific genetic signature that deviates significantly from that of KIT/PDGFRA-mutant and SDH-mutant GIST. Mutations in MEN1 and MAX genes, a neural-committed phenotype and upregulation of the master neuroendocrine regulator ASCL1, support a genetic similarity with neuroendocrine tumors, with whom they also share the great variability in oncogenic driver genes.Implications:This study provides novel insights into the biology of quadruple WT GIST that potentially resembles neuroendocrine tumors and should promote the development of specific therapeutic approaches.Mol Cancer Res; 15(5); 553-62. ©2017 AACR.
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. maria.pantaleo@unibo.it.|"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pantaleo
authors.affiliation: "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Urbini
authors.affiliation: "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Indio
authors.affiliation: Department of Pharmacy and Biotechnology, FaBit; University of Bologna, Bologna Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Ravegnini
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: "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: De Luca
authors.affiliation: "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tarantino
authors.affiliation: Department of Pharmacy and Biotechnology, FaBit; University of Bologna, Bologna Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Angelini
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gronchi
authors.affiliation: Medical Oncology, University Campus Bio-Medico, Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincenzi
authors.affiliation: Sarcoma Unit, Candiolo Cancer Institute-FPO, Torino, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grignani
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Colombo
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Fumagalli
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: Maristella
authors.initials: M
authors.lastname: Saponara
authors.affiliation: "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Ianni
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Paterini
authors.affiliation: Pathology Service, Addarii Institute of Oncology, Bologna, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Santini
authors.affiliation: Pathology Service, Addarii Institute of Oncology, Bologna, Italy.
authors.forename: M Giulia
authors.initials: MG
authors.lastname: Pirini
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceccarelli
authors.affiliation: Pathology Service, Addarii Institute of Oncology, Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Altimari
authors.affiliation: Pathology Service, Addarii Institute of Oncology, Bologna, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gruppioni
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Salvatore L
authors.initials: SL
authors.lastname: Renne
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Collini
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Stacchiotti
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: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Casali
authors.affiliation: General Surgery and Transplant Unit, Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Antonio D
authors.initials: AD
authors.lastname: Pinna
authors.affiliation: "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Astolfi
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.|"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Biasco
mesh_terms: D000328:Adult; D000368:Aged; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017423:Sequence Analysis, RNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000073359:Exome Sequencing
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C065500:ASCL1 protein, human; C499330:MAX protein, human; C105373:MEN1 protein, human; C495901:TP53 protein, human