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Originally published in Science Express on 9 January 2003
Science 31 January 2003:
Vol. 299. no. 5607, pp. 708 - 710
DOI: 10.1126/science.1079666
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Reports

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}ohsu.edu, jfletcher{at}partners.org

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Science. ISSN 0036-8075 (print), 1095-9203 (online)