Biology of Gastrointestinal Stromal Tumors: KIT Mutations and Beyond

Cancer Investigation

Volumn 22, Issue 1, 2004, Pages 106-116

  Duensing, Anette ^a,d   Heinrich, Michael C ^c   Fletcher, Christopher D M ^a   Fletcher, Jonathan A ^a,b  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b DANA FARBER CANCER INSTITUTE   (United States)

^c OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^d UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

GIST; Imatinib; KIT; Receptor tyrosine kinase; Sarcoma

Indexed keywords

IMATINIB; KIT RECEPTOR TYROSINE KINASE; PROTEIN TYROSINE KINASE; STEM CELL FACTOR; STEM CELL FACTOR RECEPTOR; TYROSINE KINASE RECEPTOR; UNCLASSIFIED DRUG;

APOPTOSIS; CANCER CELL; CELL ADHESION; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL TYPE; CHEMOTAXIS; CONFORMATIONAL TRANSITION; ENZYME ACTIVATION; GASTROINTESTINAL STROMAL TUMOR; GASTROINTESTINAL TRACT; GENE MUTATION; HUMAN; IMMUNOPHENOTYPING; INTERSTITIAL CELL OF CAJAL; MESENCHYME; METASTASIS; MORPHOLOGY; PERISTALSIS; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN PHOSPHORYLATION; REVIEW; SIGNAL TRANSDUCTION; STEM CELL;

CELL TRANSFORMATION, NEOPLASTIC; ENZYME INHIBITORS; GASTROINTESTINAL NEOPLASMS; HUMANS; NEOPLASM METASTASIS; PIPERAZINES; PROTO-ONCOGENE PROTEINS C-KIT; PYRIMIDINES; SIGNAL TRANSDUCTION; STROMAL CELLS;

EID: 1942473596     PISSN: 07357907     EISSN: None     Source Type: Journal    
DOI: 10.1081/CNV-120027585     Document Type: Review

References (72)

1. Fletcher, C.D.; Berman, J.J.; Corless, C.; Gorstein, F.; Lasota, J.; Longley, B.J.; Miettinen, M.; O'Leary, T.J.; Remotti, H.; Rubin, B.P.; Shmookler, B.; Sobin, L.H.; Weiss, S.W. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Human Pathol. 2002, 33 (5), 459-465.
2. Clary, B.M.; DeMatteo, R.P.; Lewis, J.J.; Leung, D.; Brennan, M.F. Gastrointestinal stromal tumors and leiomyosarcoma of the abdomen and retroperitoneum: a clinical comparison. Ann. Surg. Oncol. 2001, 8 (4), 290-299.
3. Emory, T.S.; Sobin, L.H.; Lukes, L.; Lee, D.H.; O'Leary, T.J. Prognosis of gastrointestinal smooth-muscle (stromal) tumors: dependence on anatomic site. Am. J. Surg. Pathol. 1999, 23 (1), 82-87.
4. Hornick, J.L.; Fletcher, C.D. Immunohistochemical staining for KIT (CD117) in soft tissue sarcomas is very limited in distribution. Am. J. Clin. Pathol. 2002, 117 (2), 188-193.
5. Golden, T.; Stout, A.P. Smooth muscle tumors of the gastrointestinal tract and retroperitoneal tissues. Surg. Gynecol. Obstet. 1941, 73, 784-810.
6. Pike, A.M.; Lloyd, R.V.; Appelman, H.D. Cell markers in gastrointestinal stromal tumors. Human Pathol. 1988, 19 (7), 830-834.
7. Hurlimann, J.; Gardiol, D. Gastrointestinal stromal tumours: an immunohistochemical study of 165 cases. Histopathology 1991, 19 (4), 311-320.
8. Newman, P.L.; Wadden, C.; Fletcher, C.D. Gastrointestinal stromal tumours: correlation of immunophenotype with clinicopathological features. J. Pathol. 1991, 164 (2), 107-117.
9. Mazur, M.T.; Clark, H.B. Gastric stromal tumors. Reappraisal of histogenesis. Am. J. Surg. Pathol. 1983, 7 (6), 507-519.
10. Kindblom, L.G.; Remotti, H.E.; Aldenborg, F.; Meis-Kindblom, J.H. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am. J. Pathol. 1998, 152 (5), 1259-1269.
11. Perez-Atayde, A.R.; Shamberger, R.C.; Kozakewich, H.W. Neuroectodermal differentiation of the gastrointestinal tumors in the Carney triad. An ultrastructural and immunohistochemical study. Am. J. Surg. Pathol. 1993, 17 (7), 706-714.
12. Lehnert, T. Gastrointestinal sarcoma (GIST)-a review of surgical management. Ann. Chir. Gynaecol. 1998, 87 (4), 297-305.
13. Huizinga, J.D.; Thuneberg, L.; Kluppel, M.; Malysz, J.; Mikkelsen, H.B.; Bernstein, A. W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 1-26-1995, 373 (6512), 347-349.
14. Kluppel, M.; Huizinga, J.D.; Malysz, J.; Bernstein, A. Developmental origin and Kit-dependent development of the interstitial cells of cajal in the mammalian small intestine. Dev. Dyn. 1998, 211 (1), 60-71.
15. Torihashi, S.; Nishi, K.; Tokutomi, Y.; Nishi, T.; Ward, S.; Sanders, K.M. Blockade of kit signaling induces transdifferentiation of interstitial cells of cajal to a smooth muscle phenotype. Gastroenterology 1999, 117 (1), 140-148.
16. Isozaki, K.; Hirota, S.; Nakama, A.; Miyagawa, J.; Shinomura, Y.; Xu, Z. ; Nomura, S.; Kitamura, Y. Disturbed intestinal movement, bile reflux to the stomach, and deficiency of c-kit-expressing cells in Ws/Ws mutant rats. Gastroenterology 1995, 109 (2), 456-464.
17. Nakama, A.; Hirota, S.; Okazaki, T.; Nagano, K.; Kawano, S.; Hori, M.; Kitamura, Y. Disturbed pyloric motility in Ws/Ws mutant rats due to deficiency of c-kit-expressing interstitial cells of Cajal. Pathol. Int. 1998, 48 (11), 843-849.
18. Majumder, S.; Brown, K.; Qiu, F.H.; Besmer, P. c-Kit protein, a transmembrane kinase: identification in tissues and characterization. Mol. Cell. Biol. 1988, 8 (11), 4896-4903.
19. Blume-Jensen, P.; Claesson-Welsh, L.; Siegbahn, A.; Zsebo, K.M.; Westermark, B.; Heldin, C.H. Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis. EMBO J. 1991, 10 (13), 4121-4128.
20. Blechman, J.M.; Lev, S.; Givol, D.; Yarden, Y. Structure-function analyses of the kit receptor for the steel factor. Stem Cells 1993, 11 (Suppl. 2), 12-21.
21. Zhang, Z.; Zhang, R.; Joachimiak, A.; Schlessinger, J.; Kong, X.P. Crystal structure of human stem cell factor: implication for stem cell factor receptor dimerization and activation. Proc. Natl. Acad. Sci. U. S. A. 7-5-2000, 97 (14), 7732-7737.
22. Linnekin, D. Early signaling pathways activated by c-Kit in hematopoietic cells. Int. J. Biochem. Cell Biol. 1999, 31 (10), 1053-1074.
23. Ashman, L.K. The biology of stem cell factor and its receptor C-kit. Int. J. Biochem. Cell Biol. 1999, 31 (10), 1037-1051.
24. Ma, Y.; Longley, B.J.; Wang, X.; Blount, J.L.; Langley, K.; Caughey, G.H. Clustering of activating mutations in c-KIT's juxtamembrane coding region in canine mast cell neoplasms. J. Invest. Dermatol. 1999, 112 (2), 165-170.
25. Kimura, A.; Nakata, Y.; Katoh, O.; Hyodo, H. c-kit Point mutation in patients with myeloproliferative disorders. Leuk. Lymphoma 1997, 25 (3-4), 281-287.
26. Gari, M.; Goodeve, A.; Wilson, G.; Winship, P.; Langabeer, S.; Linch, D. ; Vandenberghe, E.; Peake, I.; Reilly, J. c-Kit proto-oncogene exon 8 in-frame deletion plus insertion mutations in acute myeloid leukaemia. Br. J. Haematol. 1999, 105 (4), 894-900.
27. Hirota, S.; Isozaki, K.; Moriyama, Y.; Hashimoto, K.; Nishida, T.; Ishiguro, S.; Kawano, K.; Hanada, M.; Kurata, A.; Takeda, M.; Muhammad, T.G.; Matsuzawa, Y.; Kanakura, Y.; Shinomura, Y.; Kitamura, Y. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1-23-1998, 279 (5350), 577-580.
28. Nakahara, M.; Isozaki, K.; Hirota, S.; Miyagawa, J.; Hase-Sawada, N.; Taniguchi, M.; Nishida, T.; Kanayama, S.; Kitamura, Y.; Shinomura, Y.; Matsuzawa, Y. A novel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors. Gastroenterology 1998, 115 (5), 1090-1095.
29. Rubin, B.P.; Singer, S.; Tsao, C.; Duensing, A.; Lux, M.L.; Ruiz, R.; Hibbard, M.K.; Chen, C.J.; Xiao, S.; Tuveson, D.A.; Demetri, G.D.; Fletcher, C.D.; Fletcher, J.A. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res. 11-15-2001, 61 (22), 8118-8121.
30. Ernst, S.I.; Hubbs, A.E.; Przygodzki, R.M.; Emory, T.S.; Sobin, L.H.; O'Leary, T.J. KIT mutation portends poor prognosis in gastrointestinal stromal/smooth muscle tumors. Lab. Invest. 1998, 78 (12), 1633-1636.
31. Moskaluk, C.A.; Tian, Q.; Marshall, C.R.; Rumpel, C.A.; Franquemont, D.W.; Frierson, H.F., Jr. Mutations of c-kit JM domain are found in a minority of human gastrointestinal stromal tumors. Oncogene 3-11-1999, 18 (10), 1897-1902.
32. Lasota, J.; Jasinski, M.; Sarlomo-Rikala, M.; Miettinen, M. Mutations in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. Am. J. Pathol. 1999, 154 (1), 53-60.
33. Taniguchi, M.; Nishida, T.; Hirota, S.; Isozaki, K.; Ito, T.; Nomura, T. ; Matsuda, H.; Kitamura, Y. Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors. Cancer Res. 9-1-1999, 59 (17), 4297-4300.
34. Lux, M.L.; Rubin, B.P.; Biase, T.L.; Chen, C.J.; Maclure, T.; Demetri, G.; Xiao, S.; Singer, S.; Fletcher, C.D.; Fletcher, J.A. KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. Am. J. Pathol. 2000, 156 (3), 791-795.
35. Lasota, J.; Wozniak, A.; Sarlomo-Rikala, M.; Rys, J.; Kordek, R.; Nassar, A.; Sobin, L.H.; Miettinen, M. Mutations in exons 9 and 13 of KIT gene are rare events in gastrointestinal stromal tumors. A study of 200 cases. Am. J. Pathol. 2000, 157 (4), 1091-1095.
36. Hirota, S.; Nishida, T.; Isozaki, K.; Taniguchi, M.; Nakamura, J.; Okazaki, T.; Kitamura, Y. Gain-of-function mutation at the extracellular domain of KIT in gastrointestinal stromal tumours. J. Pathol. 2001, 193 (4), 505-510.
37. Sarlomo-Rikala, M.; Kovatich, A.J.; Barusevicius, A.; Miettinen, M. CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34. Mod. Path. 1998, 11 (8), 728-734.
38. Corless, C.L.; McGreevey, L.; Haley, A.; Town, A.; Heinrich, M.C. KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am. J. Pathol. 2002, 160 (5), 1567-1572.
39. Nishida, T.; Hirota, S.; Taniguchi, M.; Hashimoto, K.; Isozaki, K.; Nakamura, H.; Kanakura, Y.; Tanaka, T.; Takabayashi, A.; Matsuda, H.; Kitamura, Y. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat. Genet. 1998, 19 (4), 323-324.
40. Isozaki, K.; Terris, B.; Belghiti, J.; Schiffmann, S.; Hirota, S.; Vanderwinden, J.M. Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors. Am. J. Pathol. 2000, 157 (5), 1581-1585.
41. Hirota, S.; Okazaki, T.; Kitamura, Y.; O'Brien, P.; Kapusta, L.; Dardick, I. Cause of familial and multiple gastrointestinal autonomic nerve tumors with hyperplasia of interstitial cells of Cajal is germline mutation of the c-kit gene. Am. J. Surg. Pathol. 2000, 24 (2), 326-327.
42. Maeyama, H.; Hidaka, E.; Ota, H.; Minami, S.; Kajiyama, M.; Kuraishi, A. ; Mori, H.; Matsuda, Y.; Wada, S.; Sodeyama, H.; Nakata, S.; Kawamura, N.; Hata, S.; Watanabe, M.; Iijima, Y.; Katsuyama, T. Familial gastrointestinal stromal tumor with hyperpigmentation: association with a germline mutation of the c-kit gene. Gastroenterology 2001, 120 (1), 210-215.
43. Beghini, A.; Tibiletti, M.G.; Roversi, G.; Chiaravalli, A.M.; Serio, G.; Capella, C.; Larizza, L. Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa. Cancer 8-1-2001, 92 (3), 657-662.
44. Furitsu, T.; Tsujimura, T.; Tono, T.; Ikeda, H.; Kitayama, H.; Koshimizu, U.; Sugahara, H.; Butterfield, J.H.; Ashman, L.K.; Kanayama, Y. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J. Clin. Invest. 1993, 92 (4), 1736-1744.
45. Tsujimura, T.; Furitsu, T.; Morimoto, M.; Isozaki, K.; Nomura, S.; Matsuzawa, Y.; Kitamura, Y.; Kanakura, Y. Ligand-independent activation of c-kit receptor tyrosine kinase in a murine mastocytoma cell line P-815 generated by a point mutation. Blood 5-1-1994, 83 (9), 2619-2626.
46. Tsujimura, T.; Furitsu, T.; Morimoto, M.; Kanayama, Y.; Nomura, S.; Matsuzawa, Y.; Kitamura, Y.; Kanakura, Y. Substitution of an aspartic acid results in constitutive activation of c-kit receptor tyrosine kinase in a rat tumor mast cell line RBL-2H3. Int. Arch. Allergy Immunol. 1995, 106 (4), 377-385.
47. Tsujimura, T.; Morimoto, M.; Hashimoto, K.; Moriyama, Y.; Kitayama, H.; Matsuzawa, Y.; Kitamura, Y.; Kanakura, Y. Constitutive activation of c-kit in FMA3 murine mastocytoma cells caused by deletion of seven amino acids at the juxtamembrane domain. Blood 1-1-1996, 87 (1), 273-283.
48. Nakata, Y.; Kimura, A.; Katoh, O.; Kawaishi, K.Hyodo, H.; Abe, K.; Kuramoto, A.; Satow, Y. c-Kit point mutation of extracellular domain in patients with myeloproliferative disorders. Br. J. Haematol. 1995, 91 (3), 661-663.
49. Tian, Q.; Frierson, H.F., Jr.; Krystal, G.W.; Moskaluk, C.A. Activating c-kit gene mutations in human germ cell tumors. Am. J. Pathol. 1999, 154 (6), 1643-1647.
50. Longley, B.J., Jr.; Metcalfe, D.D.; Tharp, M.; Wang, X.; Tyrrell, L.; Lu, S.Z.; Heitjan, D.; Ma, Y. Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc. Natl. Acad. Sci. U. S. A. 2-16-1999, 96 (4), 1609-1614.
51. Boghosian, L.; Dal Cin, P.; Turc-Carel, C.; Rao, U.; Karakousis, C.; Sait, S.J.; Sandberg, A.A. Three possible cytogenetic subgroups of leiomyosarcoma. Cancer Genet. Cytogenet. 1989, 43 (1), 39-49.
52. Bardi, G.; Johansson, B.; Pandis, N.; Heim, S.; Mandahl, N.; Bak-Jensen, E.; Frederiksen, H.; Andren-Sandberg, A.; Mitelman, F. Recurrent chromosome aberrations in abdominal smooth muscle tumors. Cancer Genet. Cytogenet. 1992, 62 (1), 43-46.
53. Saunders, A.L.; Meloni, A.M.; Chen, Z.; Sandberg, A.A.; Lauwers, G.Y. Two cases of low-grade gastric leiomyosarcoma with monosomy 14 as the only change. Cancer Genet. Cytogenet. 1996, 90 (2), 184-185.
54. Wardelmann, E.; Neidt, I.; Bierhoff, E.; Speidel, N.; Manegold, C.; Fischer, H.P.; Pfeifer, U.; Pietsch, T. c-Kit mutations in gastrointestinal stromal tumors occur preferentially in the spindle rather than in the epithelioid cell variant. Mod. Path. 2002, 15 (2), 125-136.
55. Ma, Y.; Cunningham, M.E.; Wang, X.; Ghosh, I.; Regan, L.; Longley, B.J. Inhibition of spontaneous receptor phosphorylation by residues in a putative alpha-helix in the KIT intracellular juxtamembrane region. J. Biol. Chem. 5-7-1999, 274 (19), 13399-13402.
56. Paulson, R.F.; Vesely, S.; Siminovitch, K.A.; Bernstein, A. Signalling by the W/Kit receptor tyrosine kinase is negatively regulated in vivo by the protein tyrosine phosphatase Shpl. Nat. Genet. 1996, 13 (3), 309-315.
57. Kozlowski, M.; Larose, L.; Lee, F.; Le, D.M.; Rottapel, R.; Siminovitch, K.A. SHP-1 binds and negatively modulates the c-Kit receptor by interaction with tyrosine 569 in the c-Kit juxtamembrane domain. Mol. Cell. Biol. 1998, 18 (4), 2089-2099.
58. Taylor, M.L.; Metcalfe, D.D. Kit signal transduction. Hematol./Oncol. Clin. North Am. 2000, 14 (3), 517-535.
59. DeBerry, C.; Mou, S.; Linnekin, D. Stat1 associates with c-kit and is activated in response to stem cell factor. Biochem. J. 10-1-1997, 327 (Pt. 1), 73-80.
60. Piao, X.; Paulson, R.; van der Geer, P.; Pawson, T.; Bernstein, A. Oncogenic mutation in the Kit receptor tyrosine kinase alters substrate specificity and induces degradation of the protein tyrosine phosphatase SHP-1. Proc. Natl. Acad. Sci. U. S. A. 12-10-1996, 93 (25), 14665-14669.
61. Chian, R.; Young, S.; Danilkovitch-Miagkova, A.; Ronnstrand, L.; Leonard, E.; Ferrao, P.; Ashman, L.; Linnekin, D. Phosphatidylinositol 3 kinase contributes to the transformation of hematopoietic cells by the D816V c-Kit mutant. Blood 9-1-2001, 98 (5), 1365-1373.
62. Shen, Y.; Devgan, G.; Darnell, J.E., Jr.; Bromberg, J.F. Constitutively activated Stat3 protects fibroblasts from serum withdrawal and UV-induced apoptosis and antagonizes the proapoptotic effects of activated Statl. Proc. Natl. Acad. Sci. U. S. A. 2-13-2001, 98 (4), 1543-1548.
63. Lopez-Ilasaca, M.; Li, W.; Uren, A.; Yu, J.C.; Kazlauskas, A.; Gutkind, J.S.; Heidaran, M.A. Requirement of phosphatidylinositol-3 kinase for activation of JNK/SAPKs by PDGF. Biochem. Biophys. Res. Commun. 3-17-1997, 232 (2), 273-277.
64. Atfi, A.; Prunier, C.; Mazars, A.; Defachelles, A.S.; Cayre, Y.; Gespach, C.; Bourgeade, M.F. The oncogenic TEL/PDGFR beta fusion protein induces cell death through JNK/SAPK pathway. Oncogene 7-1-1999, 18 (26), 3878-3885.
65. Buchdunger, E.; Cioffi, C.L.; Law, N.; Stover, D.; Ohno-Jones, S.; Druker, B.J.; Lydon, N.B. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J. Pharmacol. Exp. Ther. 2000, 295 (1), 139-145.
66. Tuveson, D.A.; Willis, N.A.; Jacks, T.; Griffin, J.D.; Singer, S.; Fletcher, C.D.; Fletcher, J.A.; Demetri, G.D. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 8-16-2001, 20 (36), 5054-5058.
67. Joensuu, H.; Roberts, P.J.; Sarlomo-Rikala, M.; Andersson, L.C.; Tervahartiala, P.; Tuveson, D.; Silberman, S.; Capdeville, R.; Dimitrijevic, S. ; Druker, B.; Demetri, G.D. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N. Engl. J. Med. 4-5-2001, 344 (14), 1052-1056.
68. Blanke, C.D.; von Mehren, M.; Joensuu, H.; Roberts, P.J.; Eisenberg, B.; Heinrich, M.; Druker, B.; Tuveson, D.; Dimitrijevic, S.; Silberman, S.L.; Demetri, G.D. Evaluation of an oral molecularly-targeted therapy, STI571, in patients with unresectable or metastatic gastrointestinal stromal tumors (GISTs) expressing c-KIT (CD117). ASCO Proc. 2001, 20, 2.
69. van Oosterom, A.T.; Judson, I.; Verweij, J.; Stroobants, S.; Donato, di P.; Dimitrijevic, S.; Martens, M.; Webb, A.; Sciot, R.; van Glabbeke, M.; Silberman, S.; Nielsen, O.S. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 10-27-2001, 358 (9291), 1421-1423.
70. Heinrich, M.C.; Corless, C.L.; Blanke, C.; Demetri, G.D.; Joensuu, H.; von Mehren, M.; McGreevey, L.S.; Wait, C.L.; Griffith, D.; Chen, C.J.; Haley, A.; Kiese, B.; Druker, B.; Roberts, P.; Eisenberg, B.; Singer, S.; Silberman, S.; Dimitrijevic, S.; Fletcher, C.D.M.; Fletcher, J.A. Mutational status of the KIT oncoprotein correlates with the clinical responses to Imatinib mesylate (Gleevec) in patients with metastatic gastrointestinal stromal tumors (GISTs). ASCO Proc. 2002, 21.
71. Heinrich, M.C.; Corless, C.L.; Duensing, A.; McGreevey, L.; Chen, C.J.; Joseph, N.; Singer, S.; Griffith, D.J.; Haley, A.; Town, A.; Demetri, G.D.; Fletcher, C.D.; Fletcher, J.A. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003, 299 (5607), 708-710.
72. Somer, G.; Agosti, V.; Ehlers, I.; Rossi, F.; Corbacioglu, S.; Farkas, J.; Moore, M.; Manova, K.; Antonescu, C.R.; Besmer P. Gastrointestinal stromal tumors in a mouse model by targeted mutation of Kit receptor tyrosine kinase. Proc. Natl. Acad. Sci. U. S. A. 2003, 100 (11), 6706-6711.