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Science 299 (5607): 708-710

Copyright © 2003 by the American Association for the Advancement of Science

PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors

Michael C. Heinrich,1* Christopher L. Corless,2 Anette Duensing,3 Laura McGreevey,1 Chang-Jie Chen,3 Nora Joseph,3 Samuel Singer,4 Diana J. Griffith,1 Andrea Haley,1 Ajia Town,1 George D. Demetri,5 Christopher D. M. Fletcher,3 Jonathan A. Fletcher35*

Most gastrointestinal stromal tumors (GISTs) have activating mutations in the KIT receptor tyrosine kinase, and most patients with GISTs respond well to Gleevec, which inhibits KIT kinase activity. Here we show that ~35% (14 of 40) of GISTs lacking KIT mutations have intragenic activation mutations in the related receptor tyrosine kinase, platelet-derived growth factor receptor alpha  (PDGFRA). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Thus, KIT and PDGFRA mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.

1 Department of Medicine,
2 Department of Pathology, Oregon Health & Science University Cancer Institute and Portland VA Medical Center, Portland, OR 97201, USA.
3 Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA, and Harvard Medical School, Boston, MA 02115, USA.
4 Department of Surgery, Memorial Sloan-Kettering Cancer Institute, New York, NY 10021, USA.
5 Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
*   To whom correspondence should be addressed. E-mail: heinrich{at}, jfletcher{at}

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J. Clin. Oncol. 26, 5322-5325
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Imatinib Mesylate Induces Quiescence in Gastrointestinal Stromal Tumor Cells through the CDH1-SKP2-p27Kip1 Signaling Axis.
Y. Liu, S. A. Perdreau, P. Chatterjee, L. Wang, S.-F. Kuan, and A. Duensing (2008)
Cancer Res. 68, 9015-9023
   Abstract »    Full Text »    PDF »
Plexiform angiomyxoid myofibroblastic tumour: differential diagnosis of gastrointestinal stromal tumour in the stomach.
T T Rau, A Hartmann, W Dietmaier, J Schmitz, W Hohenberger, F Hofstaedter, and K Katenkamp (2008)
J. Clin. Pathol. 61, 1136-1137
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Activity of Dasatinib, a Dual SRC/ABL Kinase Inhibitor, and IPI-504, a Heat Shock Protein 90 Inhibitor, against Gastrointestinal Stromal Tumor-Associated PDGFRAD842V Mutation.
B. Dewaele, B. Wasag, J. Cools, R. Sciot, H. Prenen, P. Vandenberghe, A. Wozniak, P. Schoffski, P. Marynen, and M. Debiec-Rychter (2008)
Clin. Cancer Res. 14, 5749-5758
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Multiple Primary Sporadic Gastrointestinal Stromal Tumors in the Adult: An Underestimated Entity.
D. Gasparotto, S. Rossi, I. Bearzi, C. Doglioni, A. Marzotto, J. L. Hornick, A. Grizzo, C. Sartor, A. Mandolesi, R. Sciot, et al. (2008)
Clin. Cancer Res. 14, 5715-5721
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FIP1L1/PDGFR{alpha} synergizes with SCF to induce systemic mastocytosis in a murine model of chronic eosinophilic leukemia/hypereosinophilic syndrome.
Y. Yamada, A. Sanchez-Aguilera, E. B. Brandt, M. McBride, N. J. H. Al-Moamen, F. D. Finkelman, D. A. Williams, J. A. Cancelas, and M. E. Rothenberg (2008)
Blood 112, 2500-2507
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Distinct Gene Expression-Defined Classes of Gastrointestinal Stromal Tumor.
U. Yamaguchi, R. Nakayama, K. Honda, H. Ichikawa, T. Hasegawa, M. Shitashige, M. Ono, A. Shoji, T. Sakuma, H. Kuwabara, et al. (2008)
J. Clin. Oncol. 26, 4100-4108
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Id1 is a common downstream target of oncogenic tyrosine kinases in leukemic cells.
W. F. Tam, T.-L. Gu, J. Chen, B. H. Lee, L. Bullinger, S. Frohling, A. Wang, S. Monti, T. R. Golub, and D. G. Gilliland (2008)
Blood 112, 1981-1992
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Insulin-like growth factor (IGF) 1 and 2 help to predict disease outcome in GIST patients.
C. Braconi, R. Bracci, I. Bearzi, F. Bianchi, S. Sabato, A. Mandolesi, L. Belvederesi, S. Cascinu, N. Valeri, and R. Cellerino (2008)
Ann. Onc. 19, 1293-1298
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Characteristics of KIT-negative gastrointestinal stromal tumours and diagnostic utility of protein kinase C theta immunostaining.
H E Lee, M A Kim, H S Lee, B L Lee, and W H Kim (2008)
J. Clin. Pathol. 61, 722-729
   Abstract »    Full Text »    PDF »

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