Neurofibromatosis type 1-related gastrointestinal stromal tumors: a special reference to loss of heterozygosity at 14q and 22q

J Cancer Res Clin Oncol. 2009 Jun;135(6):791-8. doi: 10.1007/s00432-008-0514-z. Epub 2008 Nov 20.


Purpose: Multiple gastrointestinal stromal tumors (GISTs) rarely occur in patients with neurofibromatosis type 1 (NF-1). In contrast to sporadic GISTs characterized by frequent allelic losses of 1p, 14q and 22q and mutations of KIT or PDGFRA gene with the activation of the downstream RAS-MAPK pathway, the molecular pathogenetic mechanisms of NF-1-related GISTs (NF-1 GISTs) remain unclear.

Methods: Thirty-one GISTs and two foci of Cajal cell hyperplasia (CCH) were obtained from five patients with NF-1. Phospho-MAPK p44/42 expression was examined by immunohistochemical stain. KIT and PDGFRA mutations were analyzed by PCR and direct sequencing methods. Loss of heterozygosity (LOH) was analyzed by PCR-based method with microsatellite markers on 14q and 22q.

Results: Immunohistochemical expression of phospho-MAPK p44/42 was frequently found in NF-1 GISTs (23/25 cases, 92%). Neither the KIT nor PDGFRA mutation was detected in 25 NF-1 GISTs and 2 CCH. Among the informative cases, LOH was seen at 14q and 22q in 7/8 (87.5%) and 5/12 (41.7%) NF-1 GISTs, respectively. Such LOH was not detected in CCH, whereas it was detected in small GIST less than 1 cm in diameter.

Conclusions: Our results support that KIT and PDGFRA mutations are very rare events in NF-1 GIST. Rather, activation of the Ras-MAPK pathway associated with the inactivation of the NF1 gene may play an important role in the cell proliferation of NF-1 GIST. Additionally, LOH at 14q and 22q may contribute to the relatively early phase of tumor development of NF-1 GIST.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Chromosomes, Human, Pair 14 / genetics*
  • Chromosomes, Human, Pair 22 / genetics*
  • DNA Mutational Analysis
  • Duodenum / metabolism
  • Duodenum / pathology
  • Female
  • Gastrointestinal Stromal Tumors / complications
  • Gastrointestinal Stromal Tumors / genetics*
  • Gastrointestinal Stromal Tumors / metabolism
  • Humans
  • Immunohistochemistry
  • Intestine, Small / metabolism
  • Intestine, Small / pathology
  • Jejunum / metabolism
  • Jejunum / pathology
  • Loss of Heterozygosity*
  • Male
  • Microsatellite Repeats
  • Middle Aged
  • Mitogen-Activated Protein Kinase 1 / biosynthesis
  • Mitogen-Activated Protein Kinase 3 / biosynthesis
  • Mutation
  • Neurofibromatosis 1 / complications*
  • Phosphoproteins / biosynthesis
  • Proto-Oncogene Proteins c-kit / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / genetics


  • Phosphoproteins
  • Proto-Oncogene Proteins c-kit
  • Receptor, Platelet-Derived Growth Factor alpha
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3