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Science 23 January 1998:
Vol. 279. no. 5350, pp. 577 - 580
DOI: 10.1126/science.279.5350.577
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Reports

Gain-of-Function Mutations of c-kit in Human Gastrointestinal Stromal Tumors

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 dagger

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.

S. Hirota, K. Hashimoto, G. M. Tunio, Y. Kitamura, Department of Pathology, Osaka University Medical School, Yamada-oka 2-2, Suita 565, Japan.
K. Isozaki, Y. Moriyama, Y. Matsuzawa, Y. Shinomura, Department of Internal Medicine II, Osaka University Medical School, Yamada-oka 2-2, Suita 565, Japan.
T. Nishida, Department of Surgery I, Osaka University Medical School, Yamada-oka 2-2, Suita 565, Japan.
S. Ishiguro, Division of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
K. Kawano, Division of Pathology, Osaka Rosai Hospital, Sakai, Japan.
M. Hanada, Division of Pathology, Toyonaka Municipal Hospital, Toyonaka, Japan.
A. Kurata and M. Takeda, Division of Pathology, Osaka National Hospital, Osaka, Japan.
Y. Kanakura, Department of Hematology/Oncology, Osaka University Medical School, Yamada-oka 2-2, Suita 565, Japan.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: kitamura{at}patho.med.osaka-u.ac.jp

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Growth suppression of human mast cells expressing constitutively active c-kit receptors by JNK inhibitor SP600125..
B. Wang, J. Tsukada, T. Higashi, T. Mizobe, A. Matsuura, F. Mouri, N. Sawamukai, C. Ra, and Y. Tanaka (2006)
Genes Cells 11, 983-992
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A CSF-1 receptor kinase inhibitor targets effector functions and inhibits pro-inflammatory cytokine production from murine macrophage populations.
K. M. Irvine, C. J. Burns, A. F. Wilks, S. Su, D. A. Hume, and M. J. Sweet (2006)
FASEB J 20, 1921-1923
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Microsatellite DNA Alterations of Gastrointestinal Stromal Tumors Are Predictive for Outcome.
P. Schurr, S. Wolter, J. Kaifi, U. Reichelt, H. Kleinhans, R. Wachowiak, E. Yekebas, T. Strate, V. Kalinin, R. Simon, et al. (2006)
Clin. Cancer Res. 12, 5151-5157
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Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor.
F. Rossi, I. Ehlers, V. Agosti, N. D. Socci, A. Viale, G. Sommer, Y. Yozgat, K. Manova, C. R. Antonescu, and P. Besmer (2006)
PNAS 103, 12843-12848
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Adverse Prognostic Significance of KIT Mutations in Adult Acute Myeloid Leukemia With inv(16) and t(8;21): A Cancer and Leukemia Group B Study.
P. Paschka, G. Marcucci, A. S. Ruppert, K. Mrozek, H. Chen, R. A. Kittles, T. Vukosavljevic, D. Perrotti, J. W. Vardiman, A. J. Carroll, et al. (2006)
J. Clin. Oncol. 24, 3904-3911
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Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells.
M. Gabillot-Carre, Y. Lepelletier, M. Humbert, P. de Sepuvelda, N. B. Hamouda, J. P. Zappulla, R. Liblau, A. Ribadeau-Dumas, F. Machavoine, S. Letard, et al. (2006)
Blood 108, 1065-1072
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Genomic approaches to lung cancer..
R. K. Thomas, B. Weir, and M. Meyerson (2006)
Clin. Cancer Res. 12, 4384s-4391s
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Flavopiridol Targets c-KIT Transcription and Induces Apoptosis in Gastrointestinal Stromal Tumor Cells.
E. B. Sambol, G. Ambrosini, R. C. Geha, P. T. Kennealey, P. DeCarolis, R. O'Connor, Y. V. Wu, M. Motwani, J.-H. Chen, G. K. Schwartz, et al. (2006)
Cancer Res. 66, 5858-5866
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Results of a Single-Center Experience With Resection and Ablation for Sarcoma Metastatic to the Liver.
T. M. Pawlik, J.-N. Vauthey, E. K. Abdalla, R. E. Pollock, L. M. Ellis, and S. A. Curley (2006)
Arch Surg 141, 537-544
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An update on molecular genetics of gastrointestinal stromal tumours..
L Tornillo and L M Terracciano (2006)
J. Clin. Pathol. 59, 557-563
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Pitfalls in immunohistochemical assessment of EGFR expression in soft tissue sarcomas.
C Kersting, J Packeisen, B Leidinger, B Brandt, R von Wasielewski, W Winkelmann, P J van Diest, G Gosheger, and H Buerger (2006)
J. Clin. Pathol. 59, 585-590
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Cancer and leukemia group B gastrointestinal cancer committee..
R. M. Goldberg, D. Niedzwiecki, M. Bertagnolli, A. W. Blackstock, J. E. Tepper, and R. J. Mayer (2006)
Clin. Cancer Res. 12, 3589s-3595s
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Activation of FIP1L1-PDGFR{alpha} requires disruption of the juxtamembrane domain of PDGFR{alpha} and is FIP1L1-independent.
E. H. Stover, J. Chen, C. Folens, B. H. Lee, N. Mentens, P. Marynen, I. R. Williams, D. G. Gilliland, and J. Cools (2006)
PNAS 103, 8078-8083
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Surgical Management of Advanced Gastrointestinal Stromal Tumors After Treatment With Targeted Systemic Therapy Using Kinase Inhibitors.
C. P. Raut, M. Posner, J. Desai, J. A. Morgan, S. George, D. Zahrieh, C. D.M. Fletcher, G. D. Demetri, and M. M. Bertagnolli (2006)
J. Clin. Oncol. 24, 2325-2331
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Therapeutic Effect of Imatinib in Gastrointestinal Stromal Tumors: AKT Signaling Dependent and Independent Mechanisms..
C. Tarn, Y. V. Skorobogatko, T. Taguchi, B. Eisenberg, M. von Mehren, and A. K. Godwin (2006)
Cancer Res. 66, 5477-5486
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Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML.
C. Reindl, K. Bagrintseva, S. Vempati, S. Schnittger, J. W. Ellwart, K. Wenig, K.-P. Hopfner, W. Hiddemann, and K. Spiekermann (2006)
Blood 107, 3700-3707
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Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients.
O. Maertens, H. Prenen, M. Debiec-Rychter, A. Wozniak, R. Sciot, P. Pauwels, I. De Wever, J. R. Vermeesch, T. de Raedt, A. De Paepe, et al. (2006)
Hum. Mol. Genet. 15, 1015-1023
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Polyclonal Evolution of Multiple Secondary KIT Mutations in Gastrointestinal Stromal Tumors under Treatment with Imatinib Mesylate..
E. Wardelmann, S. Merkelbach-Bruse, K. Pauls, N. Thomas, H.-U. Schildhaus, T. Heinicke, N. Speidel, T. Pietsch, R. Buettner, D. Pink, et al. (2006)
Clin. Cancer Res. 12, 1743-1749
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YM-359445, an Orally Bioavailable Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor, Has Highly Potent Antitumor Activity against Established Tumors.
N. Amino, Y. Ideyama, M. Yamano, S. Kuromitsu, K. Tajinda, K. Samizu, H. Hisamichi, A. Matsuhisa, K. Shirasuna, M. Kudoh, et al. (2006)
Clin. Cancer Res. 12, 1630-1638
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Gastrointestinal Stromal Tumor: Role of CT in Diagnosis and in Response Evaluation and Surveillance after Treatment with Imatinib..
X. Hong, H. Choi, E. M. Loyer, R. S. Benjamin, J. C. Trent, and C. Charnsangavej (2006)
RadioGraphics 26, 481-495
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A Case Report of a Spontaneous Gastrointestinal Stromal Tumor (GIST) Occurring in a F344 Rat.
H. Fujimoto, M. Shibutani, K. Kuroiwa, K. Inoue, G.-H. Woo, M. U, and M. Hirose (2006)
Toxicol Pathol 34, 164-167
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Somatic Mutations Lead to an Oncogenic Deletion of Met in Lung Cancer.
M. Kong-Beltran, S. Seshagiri, J. Zha, W. Zhu, K. Bhawe, N. Mendoza, T. Holcomb, K. Pujara, J. Stinson, L. Fu, et al. (2006)
Cancer Res. 66, 283-289
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Dasatinib (BMS-354825), a Dual SRC/ABL Kinase Inhibitor, Inhibits the Kinase Activity of Wild-Type, Juxtamembrane, and Activation Loop Mutant KIT Isoforms Associated with Human Malignancies.
M. M. Schittenhelm, S. Shiraga, A. Schroeder, A. S. Corbin, D. Griffith, F. Y. Lee, C. Bokemeyer, M. W.N. Deininger, B. J. Druker, and M. C. Heinrich (2006)
Cancer Res. 66, 473-481
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Management of Gastrointestinal Stromal Tumors in the Imatinib Era: Selected Case Studies.
R. S. Benjamin, C. D. Blanke, J.-Y. Blay, S. Bonvalot, and B. Eisenberg (2006)
Oncologist 11, 9-20
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