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

  • Hidetaka Yamamoto
  • Taro Tobo
  • Mari Nakamori
  • Masakazu Imamura
  • Aya Kojima
  • Yoshinao Oda
  • Norimoto Nakamura
  • Tomonari Takahira
  • Takashi Yao
  • Masazumi Tsuneyoshi
Original Paper

DOI: 10.1007/s00432-008-0514-z

Cite this article as:
Yamamoto, H., Tobo, T., Nakamori, M. et al. J Cancer Res Clin Oncol (2009) 135: 791. doi:10.1007/s00432-008-0514-z

Abstract

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.

Keywords

Gastrointestinal stromal tumor Neurofibromatosis type 1 KIT Loss of heterozygosity MAPK 

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Hidetaka Yamamoto
    • 1
  • Taro Tobo
    • 1
  • Mari Nakamori
    • 1
  • Masakazu Imamura
    • 1
  • Aya Kojima
    • 1
  • Yoshinao Oda
    • 1
  • Norimoto Nakamura
    • 1
  • Tomonari Takahira
    • 1
  • Takashi Yao
    • 1
  • Masazumi Tsuneyoshi
    • 1
  1. 1.Department of Anatomic Pathology, Pathological SciencesGraduate School of Medical Sciences, Kyushu UniversityFukuokaJapan