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Seiichi Hirota,* Koji Isozaki,* Yasuhiro Moriyama, Koji Hashimoto, Toshirou Nishida, Shingo Ishiguro, Kiyoshi Kawano, Masato Hanada, Akihiko Kurata, Masashi Takeda, Ghulam Muhammad Tunio, Yuji Matsuzawa, Yuzuru Kanakura, Yasuhisa Shinomura, Yukihiko Kitamura*'
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract, but their molecular etiology and cellular origin are unknown. Sequencing of c-kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains. All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF). Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development. GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34.
The c-kit proto-oncogene encodes a type III receptor tyrosine kinase (KIT) (1), the ligand of which is SCF (2). SCF-KIT interaction is essential for development of melanocytes, erythrocytes, germ cells, mast cells and ICCs (3, 4). Gain-of-function mutations of the c-kit gene have been found in several tumor mast cell lines of rodents and humans (5, 6) and in mast cell tumors of humans (7). Here we investigate the mutational status of c-kit in mesenchymal tumors of the human gastrointestinal (GI) tract. We collected 58 mesenchymal tumors that developed in the GI wall (4 in the esophagus, 36 in the stomach, 14 in the small intestine, and 4 in the large intestine). KIT expression was examined by immunohistochemistry (8). Eight authentic leiomyomas and an authentic schwannoma did not express KIT. The remaining 49 mesenchymal tumors were diagnosed as gastrointestinal stromal tumors (GISTs), and 94% (46/ 49) of these expressed KIT. Examination of these tumors for expression of CD34, which is a reliable marker for GISTs (9), revealed that 82% (40/49) were CD34-positive, and 78% (38/49) were positive for both KIT and CD34 (Fig. 1, A to I). Three of five KITnegative GISTs were also CD34-negative.
We compared the immunohistochemical characteristics of GISTs with those of ICCs, cells that regulate autonomous contraction of the GI tract (4)....