Abstract
The c-kit gene encodes a transmembrane receptor kinase (KIT) which is expressed in the majority of human gastrointestinal stromal tumors (GISTs), a subtype of gastrointestinal mesenchymal neoplasms. A previous study identified mutations in the juxtamembrane (JM) domain of c-kit in five of six GISTs (Science 279: 577, 1998). To better define the frequency and spectrum of c-kit gene mutations in mesenchymal neoplasms of the GI tract that had been characterized for KIT protein expression, we examined archived tissue samples for mutations in the JM domain by PCR amplification and DNA sequencing. c-kit JM domain mutations were found in nine of 56 mesenchymal tumors (46 GISTs, eight leiomyomas, two leiomyosarcomas) and occurred exclusively in GISTs (21%). Seven of the nine mutations consisted of intragenic deletions of one to 19 codons. There was one insertion mutation that added 12 codons and one missense mutation (Val560Asp). None of the mutations disrupted the downstream reading frame of the gene. The single missense mutation (Val560Asp) is very similar to the only other missense mutation reported in GISTs (Val599Asp). Of the 46 GISTs, 43 were strongly positive for KIT protein expression and negative for diffuse expression of desmin. Neither KIT expression nor gene mutations were found in gastrointestinal leiomyomas or leiomyosarcomas. We conclude that mutation of the c-kit JM domain does not occur in gastrointestinal mesenchymal neoplasms with well developed-smooth muscle differentiation, and is restricted to GISTs. However, since these mutations are only found in a minority of GISTs, further investigation into the mechanisms of c-kit gene activation in this group of neoplasms is warranted.
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Acknowledgements
We thank Mark Clem for his assistance with histologic sectioning and immunohistochemical staining. This publication was supported by grant number 5K08CA74431-02 from the National Cancer Institute. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
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Moskaluk, C., Tian, Q., Marshall, C. et al. Mutations of c-kit JM domain are found in a minority of human gastrointestinal stromal tumors. Oncogene 18, 1897–1902 (1999). https://doi.org/10.1038/sj.onc.1202496
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DOI: https://doi.org/10.1038/sj.onc.1202496
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