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

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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.

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Acknowledgments

This study was supported in part by a Grant-in-Aid for cancer research from the Fukuoka Cancer Society, Fukuoka, Japan (H. Yamamoto) and by a Grant-in-Aid for Scientific Research from the Japan Society of the Promotion of Science (18790248, H. Yamamoto; 18590332, Y. Oda), Tokyo, Japan.

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Authors and Affiliations

  1. Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan

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

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  1. Hidetaka Yamamoto
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  2. Taro Tobo
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  3. Mari Nakamori
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  4. Masakazu Imamura
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  10. Masazumi Tsuneyoshi
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Correspondence to Hidetaka Yamamoto.

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Yamamoto, H., Tobo, T., Nakamori, M. et al. Neurofibromatosis type 1-related gastrointestinal stromal tumors: a special reference to loss of heterozygosity at 14q and 22q. J Cancer Res Clin Oncol 135, 791–798 (2009). https://doi.org/10.1007/s00432-008-0514-z

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  • DOI: https://doi.org/10.1007/s00432-008-0514-z

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