title: Quadruple-Negative GIST Is a Sentinel for Unrecognized Neurofibromatosis Type 1 Syndrome.
abstract: OBJECTIVE
  The majority of gastrointestinal stromal tumors (GIST) are driven by KIT, PDGFRA, or, less commonly, BRAF mutations, and SDH gene inactivation is involved in a limited fraction of gastric lesions. However, about 10% of GISTs are devoid of any of such alterations and are poorly responsive to standard treatments. This study aims to shed light on the molecular drivers of quadruple-negative GISTs.
  
  
  METHODS
  Twenty-two sporadic quadruple-negative GISTs with no prior association with Neurofibromatosis Type 1 syndrome were molecularly profiled for a panel of genes belonging to tyrosine kinase pathways or previously implicated in GISTs. For comparison purposes, 24 GISTs carrying KIT, PDGFRA, or SDH gene mutations were also analyzed. Molecular findings were correlated to clinicopathologic features.
  
  
  RESULTS
  Most quadruple-negative GISTs featured intestinal localization, with a female predilection. About 60% (13/22) of quadruple-negative tumors carried NF1 pathogenic mutations, often associated with biallelic inactivation. The analysis of normal tissues, available in 11 cases, indicated the constitutional nature of the NF1 mutation in 7 of 11 cases, unveiling an unrecognized Neurofibromatosis Type 1 syndromic condition. Multifocality and a multinodular pattern of growth were common findings in NF1-mutated quadruple-negative GISTs.
  
  
  CONCLUSIONS
  NF1 gene mutations are frequent in quadruple-negative GISTs and are often constitutional, indicating that a significant fraction of patients with apparently sporadic quadruple-negative GISTs are affected by unrecognized Neurofibromatosis Type 1 syndrome. Hence, a diagnosis of quadruple-negative GIST, especially if multifocal or with a multinodular growth pattern and a nongastric location, should alert the clinician to a possible Neurofibromatosis Type 1 syndromic condition. Clin Cancer Res; 23(1); 273-82. ©2016 AACR.
authors.affiliation: Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gasparotto
authors.affiliation: Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Polano
authors.affiliation: Department of Pathology and Molecular Biology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tamborini
authors.affiliation: Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Lorenzetto
authors.affiliation: Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Sbaraglia
authors.affiliation: Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Mondello
authors.affiliation: Department of Surgery, Treviso General Hospital, Treviso, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Massani
authors.affiliation: Department of Oncology, Treviso General Hospital, Treviso, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Lamon
authors.affiliation: Department of Internal Medicine, Ospedali Riuniti di Ancona, Ancona, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Bracci
authors.affiliation: Department of Internal Medicine, Ospedali Riuniti di Ancona, Ancona, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mandolesi
authors.affiliation: Medical Genetics Unit, Treviso General Hospital, Treviso, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Frate
authors.affiliation: Clinical Genetics Service, Bolzano General Hospital, Bolzano/Bozen, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Stanzial
authors.affiliation: Department of Surgery, Vipiteno General Hospital, Vipiteno/Sterzing, Italy.
authors.forename: Jerin
authors.initials: J
authors.lastname: Agaj
authors.affiliation: Department of Pathology, Bolzano General Hospital, Bolzano/Bozen, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Mazzoleni
authors.affiliation: Department of Pathology and Molecular Biology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
authors.affiliation: Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gronchi
authors.affiliation: Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy.
authors.forename: Angelo Paolo
authors.initials: AP
authors.lastname: Dei Tos
authors.affiliation: Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano, Italy. maestro@cro.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Maestro
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D014408:Biomarkers, Tumor; D004252:DNA Mutational Analysis; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D016514:Genes, Neurofibromatosis 1; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009456:Neurofibromatosis 1 / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D048493:Proto-Oncogene Proteins B-raf