Quadruple-negative GIST is a sentinel for unrecognized neurofibromatosis type 1 syndrome

D. Gasparotto, S. Rossi, M. Polano, E. Tamborini, E. Lorenzetto, M. Sbaraglia, A. Mondello, M. Massani, S. Lamon, R. Bracci, A. Mandolesi, E. Frate, F. Stanzial, J. Agaj, G. Mazzoleni, S. Pilotti, A. Gronchi, A.P. Dei Tos, R. Maestro

Research output: Contribution to journalArticlepeer-review


Purpose: 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. Experimental Design: 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. ©2016 AACR.
Original languageEnglish
Pages (from-to)273-282
Number of pages10
JournalClinical Cancer Research
Issue number1
Publication statusPublished - 2017


  • adult
  • aged
  • Article
  • cancer growth
  • clinical article
  • clinical feature
  • controlled study
  • female
  • gastrointestinal stromal tumor
  • gene
  • gene mutation
  • human
  • human tissue
  • KIT gene
  • male
  • middle aged
  • multiple cancer
  • neurofibromatosis type 1
  • NF1 gene
  • PDGFRA gene
  • quadruple negative gastrointestinal stromal tumor
  • SDH gene
  • sex difference
  • tumor localization
  • very elderly
  • allele
  • dna mutational analysis
  • genetics
  • genotype
  • high throughput sequencing
  • mortality
  • mutation
  • prognosis
  • tumor suppressor gene
  • B Raf kinase
  • platelet derived growth factor alpha receptor
  • stem cell factor receptor
  • tumor marker
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Biomarkers, Tumor
  • DNA Mutational Analysis
  • Female
  • Gastrointestinal Stromal Tumors
  • Genes, Neurofibromatosis 1
  • Genotype
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Neurofibromatosis 1
  • Prognosis
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-kit
  • Receptor, Platelet-Derived Growth Factor alpha


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