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PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors
Michael C. Heinrich,1*Christopher L. Corless,2Anette Duensing,3Laura McGreevey,1Chang-Jie Chen,3Nora Joseph,3Samuel Singer,4Diana J. Griffith,1Andrea Haley,1Ajia Town,1George D. Demetri,5Christopher D. M. Fletcher,3Jonathan A. Fletcher35*
Most gastrointestinal stromal tumors (GISTs) have activating
mutations in the KIT receptor tyrosine kinase, and most patientswith
GISTs respond well to Gleevec, which inhibits KIT kinaseactivity. Here
we show that ~35% (14 of 40) of GISTs lacking KITmutations have intragenic activation mutations in the relatedreceptor
tyrosine kinase, platelet-derived growth factor receptor (PDGFRA). Tumors expressing KIT or PDGFRA oncoproteins wereindistinguishable with respect to activation of downstream signalingintermediates and cytogenetic changes associated with tumor
progression.Thus, KIT and PDGFRA mutations
appear to be alternative and mutuallyexclusive 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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Oncologist
11, 9-20
|Abstract »|Full Text »|PDF »
Cytogenetic Confirmation of a Gastrointestinal Stromal Tumor and Ewing Sarcoma/Primitive Neuroectodermal Tumor in a Single Patient.
S. Kondo, U. Yamaguchi, S. Sakurai, Y. Ikezawa, H. Chuman, U. Tateishi, K. Furuta, and T. Hasegawa (2005)
Jpn. J. Clin. Oncol.
35, 753-756
|Abstract »|Full Text »|PDF »
Sequence survey of receptor tyrosine kinases reveals mutations in glioblastomas.
V. Rand, J. Huang, T. Stockwell, S. Ferriera, O. Buzko, S. Levy, D. Busam, K. Li, J. B. Edwards, C. Eberhart, et al. (2005)
PNAS
102, 14344-14349
|Abstract »|Full Text »|PDF »
Prognostic Role of E2F1 and Members of the CDKN2A Network in Gastrointestinal Stromal Tumors.
F. Haller, B. Gunawan, A. von Heydebreck, S. Schwager, H.-J. Schulten, J. Wolf-Salgo, C. Langer, G. Ramadori, H. Sultmann, and L. Fuzesi (2005)
Clin. Cancer Res.
11, 6589-6597
|Abstract »|Full Text »|PDF »
Deletions Affecting Codons 557-558 of the c-KIT Gene Indicate a Poor Prognosis in Patients With Completely Resected Gastrointestinal Stromal Tumors: A Study by the Spanish Group for Sarcoma Research (GEIS).
J. Martin, A. Poveda, A. Llombart-Bosch, R. Ramos, J. A. Lopez-Guerrero, J. G. del Muro, J. Maurel, S. Calabuig, A. Gutierrez, J. L. G. de Sande, et al. (2005)
J. Clin. Oncol.
23, 6190-6198
|Abstract »|Full Text »|PDF »
The value of c-kit mutational analysis in a cytokeratin positive gastrointestinal stromal tumour.
G Rossi, G Sartori, R Valli, F Bertolini, N Bigiani, L Schirosi, A Cavazza, and G Luppi (2005)
J. Clin. Pathol.
58, 991-993
|Abstract »|Full Text »|PDF »
Soft-Tissue Sarcomas in Adults.
M. A. Clark, C. Fisher, I. Judson, and J. M. Thomas (2005)
N. Engl. J. Med.
353, 701-711
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PDGFRA Mutations in Gastrointestinal Stromal Tumors: Frequency, Spectrum and In Vitro Sensitivity to Imatinib.
C. L. Corless, A. Schroeder, D. Griffith, A. Town, L. McGreevey, P. Harrell, S. Shiraga, T. Bainbridge, J. Morich, and M. C. Heinrich (2005)
J. Clin. Oncol.
23, 5357-5364
|Abstract »|Full Text »|PDF »
A Knock-In Mouse Model of Gastrointestinal Stromal Tumor Harboring Kit K641E.
B. P. Rubin, C. R. Antonescu, J. P. Scott-Browne, M. L. Comstock, Y. Gu, M. R. Tanas, C. B. Ware, and J. Woodell (2005)
Cancer Res.
65, 6631-6639
|Abstract »|Full Text »|PDF »
Temporal quantitation of mutant Kit tyrosine kinase signaling attenuated by a novel thiophene kinase inhibitor OSI-930.
F. Petti, A. Thelemann, J. Kahler, S. McCormack, L. Castaldo, T. Hunt, L. Nuwaysir, L. Zeiske, H. Haack, L. Sullivan, et al. (2005)
Mol. Cancer Ther.
4, 1186-1197
|Abstract »|Full Text »|PDF »
Introduction to a Cancer Symposium for the Practitioner.
A. Tefferi, S. V. Rajkumar, and A. A. Adjei (2005)
Mayo Clin. Proc.
80, 1085-1086
|PDF »
Tyrosine Kinases as Targets for Cancer Therapy.
D. S. Krause and R. A. Van Etten (2005)
N. Engl. J. Med.
353, 172-187
|Full Text »|PDF »
Homozygous Deletions and Chromosome Amplifications in Human Lung Carcinomas Revealed by Single Nucleotide Polymorphism Array Analysis.
X. Zhao, B. A. Weir, T. LaFramboise, M. Lin, R. Beroukhim, L. Garraway, J. Beheshti, J. C. Lee, K. Naoki, W. G. Richards, et al. (2005)
Cancer Res.
65, 5561-5570
|Abstract »|Full Text »|PDF »
The location of KIT and PDGFRA gene mutations in gastrointestinal stromal tumours is site and phenotype associated.
R Penzel, S Aulmann, M Moock, M Schwarzbach, R J Rieker, and G Mechtersheimer (2005)
J. Clin. Pathol.
58, 634-639
|Abstract »|Full Text »|PDF »
Acquired Resistance to Imatinib in Gastrointestinal Stromal Tumor Occurs Through Secondary Gene Mutation.
C. R. Antonescu, P. Besmer, T. Guo, K. Arkun, G. Hom, B. Koryotowski, M. A. Leversha, P. D. Jeffrey, D. Desantis, S. Singer, et al. (2005)
Clin. Cancer Res.
11, 4182-4190
|Abstract »|Full Text »|PDF »
Mapping Molecular Networks Using Proteomics: A Vision for Patient-Tailored Combination Therapy.
E. F. Petricoin III, V. E. Bichsel, V. S. Calvert, V. Espina, M. Winters, L. Young, C. Belluco, B. J. Trock, M. Lippman, D. A. Fishman, et al. (2005)
J. Clin. Oncol.
23, 3614-3621
|Abstract »|Full Text »|PDF »
Analysis of KIT Mutations in Sporadic and Familial Gastrointestinal Stromal Tumors: Therapeutic Implications through Protein Modeling.
C. Tarn, E. Merkel, A. A. Canutescu, W. Shen, Y. Skorobogatko, M. J. Heslin, B. Eisenberg, R. Birbe, A. Patchefsky, R. Dunbrack, et al. (2005)
Clin. Cancer Res.
11, 3668-3677
|Abstract »|Full Text »|PDF »
Autocrine- and paracrine-activated receptor tyrosine kinases in classic Hodgkin lymphoma.
C. Renne, K. Willenbrock, R. Kuppers, M.-L. Hansmann, and A. Brauninger (2005)
Blood
105, 4051-4059
|Abstract »|Full Text »|PDF »
KIT-positive Gastrointestinal Stromal Tumor in a 22-year-old Male Chimpanzee (Pan troglodites).
G. A. Saturday, J. Lasota, D. Frost, K. B. Brasky, G. Hubbard, and M. Miettinen (2005)
Vet. Pathol.
42, 362-365
|Abstract »|Full Text »|PDF »
Familial Gastrointestinal Stromal Tumor Syndrome: Phenotypic and Molecular Features in a Kindred.
F. P. Li, J. A. Fletcher, M. C. Heinrich, J. E. Garber, S. E. Sallan, C. Curiel-Lewandrowski, A. Duensing, M. van de Rijn, L. E. Schnipper, and G. D. Demetri (2005)
J. Clin. Oncol.
23, 2735-2743
|Abstract »|Full Text »|PDF »
Sequential Blockade of Oncogenic Kinases.
R. Chen and W. Plunkett (2005)
Am. Assoc. Cancer Res. Educ. Book
2005, 344-348
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Targeting the platelet-derived growth factor receptor {alpha} with a neutralizing human monoclonal antibody inhibits the growth of tumor xenografts: Implications as a potential therapeutic target.
N. Loizos, Y. Xu, J. Huber, M. Liu, D. Lu, B. Finnerty, R. Rolser, A. Malikzay, A. Persaud, E. Corcoran, et al. (2005)
Mol. Cancer Ther.
4, 369-379
|Abstract »|Full Text »|PDF »
(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.
