title: Neurofibromatosis type 1-related gastrointestinal stromal tumors: a special reference to loss of heterozygosity at 14q and 22q.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan. hidetaka@surgpath.med.kyushu-u.ac.jp
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Taro
authors.initials: T
authors.lastname: Tobo
authors.forename: Mari
authors.initials: M
authors.lastname: Nakamori
authors.forename: Masakazu
authors.initials: M
authors.lastname: Imamura
authors.forename: Aya
authors.initials: A
authors.lastname: Kojima
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
authors.forename: Norimoto
authors.initials: N
authors.lastname: Nakamura
authors.forename: Tomonari
authors.initials: T
authors.lastname: Takahira
authors.forename: Takashi
authors.initials: T
authors.lastname: Yao
authors.forename: Masazumi
authors.initials: M
authors.lastname: Tsuneyoshi
mesh_terms: D000328:Adult; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004386:Duodenum / Q000378:metabolism / Q000473:pathology; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D007583:Jejunum / Q000378:metabolism / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis; D009154:Mutation; D009456:Neurofibromatosis 1 / Q000150:complications*; D010750:Phosphoproteins / Q000096:biosynthesis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics
chemical_list: D010750:Phosphoproteins; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3