Journal ArticleDOI
Biology of gastrointestinal stromal tumors.
TLDR
The rapid progress that has established GIST as a model for understanding the role of oncogenic kinase mutations in human tumorigenesis is charted and a molecular-based classification of GIST is proposed.Abstract:
Once a poorly defined pathologic oddity, in recent years, gastrointestinal stromal tumor (GIST) has emerged as a distinct oncogenetic entity that is now center stage in clinical trials of kinase-targeted therapies. This review charts the rapid progress that has established GIST as a model for understanding the role of oncogenic kinase mutations in human tumorigenesis. Approximately 80% to 85% of GISTs harbor activating mutations of the KIT tyrosine kinase. In a series of 322 GISTs (including 140 previously published cases) studied by the authors in detail, mutations in the KIT gene occurred with decreasing frequency in exons 11 (66.1%), 9 (13%), 13 (1.2%), and 17 (0.6%). In the same series, a subset of tumors had mutations in the KIT-related kinase gene PDGF receptor alpha (PDGFRA), which occurred in either exon 18 (5.6%) or 12 (1.5%). The remainder of GISTs (12%) were wild type for both KIT and PDGFRA. Comparative studies of KIT-mutant, PDGFRA-mutant, and wild-type GISTs indicate that there are many similarities between these groups of tumors but also important differences. In particular, the responsiveness of GISTs to treatment with the kinase inhibitor imatinib varies substantially depending on the exonic location of the KIT or PDGFRA mutation. Given these differences, which have implications both for the diagnosis and treatment of GISTs, we propose a molecular-based classification of GIST. Recent studies of familial GIST, pediatric GIST, and variant forms of GIST related to Carney's triad and neurofibromatosis type 1 are discussed in relationship to this molecular classification. In addition, the role of mutation screening in KIT and PDGFRA as a diagnostic and prognostic aid is emphasized in this review.read more
Citations
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Journal ArticleDOI
Gastrointestinal Stromal Tumors: Review on Morphology, Molecular Pathology, Prognosis, and Differential Diagnosis
Markku Miettinen,Jerzy Lasota +1 more
TL;DR: GISTs usually occur in older adults and rarely in children in the second decade and are believed to originate from interstitial cells of Cajal or related stem cells; small intestinal tumors behave more aggressively than gastric tumors with similar parameters.
Journal ArticleDOI
Gastrointestinal stromal tumour
Brian P. Rubin,Michael Heinrich,Michael Heinrich,Christopher L. Corless,Christopher L. Corless +4 more
TL;DR: Targeting activated proteins with imatinib mesylate, a small-molecule kinase inhibitor, has proven useful in the treatment of recurrent or metastatic gastrointestinal stromal tumours and is now being tested as an adjuvant or neoadjuvant.
Journal ArticleDOI
KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours
Maria Debiec-Rychter,Raf Sciot,Axel Le Cesne,Marcus Schlemmer,Peter Hohenberger,Allan T. van Oosterom,Jean-Yves Blay,Serge Leyvraz,Michel Stul,Paolo G. Casali,John Zalcberg,Jaap Verweij,Martine Van Glabbeke,Anne Hagemeijer,Ian Judson +14 more
TL;DR: It is concluded that tumour genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTs, with KIT exon 9 mutant patients benefiting the most from the 800 mg daily dose of the drug.
Journal ArticleDOI
PDGFRA Mutations in Gastrointestinal Stromal Tumors: Frequency, Spectrum and In Vitro Sensitivity to Imatinib
Christopher L. Corless,Arin Schroeder,Diana J. Griffith,Ajia Town,Laura McGreevey,Patina Harrell,Sharon Shiraga,Troy Bainbridge,Jason Morich,Michael Heinrich +9 more
TL;DR: It is suggested that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors.
Journal ArticleDOI
Molecular Correlates of Imatinib Resistance in Gastrointestinal Stromal Tumors
Michael Heinrich,Christopher L. Corless,Charles D. Blanke,George D. Demetri,Heikki Joensuu,Peter J. Roberts,Burton L. Eisenberg,Margaret von Mehren,Christopher D.M. Fletcher,Katrin Sandau,Karen McDougall,Wen-Bin Ou,Chang Jie Chen,Jonathan A. Fletcher +13 more
TL;DR: Using RNAi technology, it is demonstrated that imatinib-resistant GIST cells remain dependent on KIT kinase activity for activation of critical downstream signaling pathways, which has implications for future approaches to the growing problem ofImatinib resistance in patients with advanced GISTs.
References
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Journal ArticleDOI
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 +14 more
TL;DR: Sequencing of c-kit complementary DNA from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains, suggesting that the mutations contribute to tumor development.
Journal ArticleDOI
Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.
George D. Demetri,Margaret von Mehren,Charles D. Blanke,Annick D. Van den Abbeele,Burton L. Eisenberg,Peter J. Roberts,Michael Heinrich,David A. Tuveson,Samuel Singer,Milos J. Janicek,Jonathan A. Fletcher,Stuart G. Silverman,Sandra Silberman,Renaud Capdeville,Beate Kiese,Bin Peng,Sasa Dimitrijevic,Brian J. Druker,Christopher L. Corless,Christopher D.M. Fletcher,Heikki Joensuu +20 more
TL;DR: Imatinib induced a sustained objective response in more than half of patients with an advanced unresectable or metastatic gastrointestinal stromal tumor, indicating that inhibition of the KIT signal-transduction pathway is a promising treatment for advanced gastrointestinalStromal tumors, which resist conventional chemotherapy.
Journal ArticleDOI
Diagnosis of gastrointestinal stromal tumors: A consensus approach.
Christopher D.M. Fletcher,Jules J. Berman,Christopher L. Corless,Fred Gorstein,Jerzy Lasota,B. Jack Longley,Markku Miettinen,Timothy J. O'Leary,Helen Remotti,Brian P. Rubin,Barry M. Shmookler,Leslie H. Sobin,Sharon W. Weiss +12 more
TL;DR: Key elements of the consensus are the defining role of KIT immunopositivity in diagnosis and a proposed scheme for estimating metastatic risk in these lesions, based on tumor size and mitotic count, recognizing that it is probably unwise to use the definitive term "benign" for any GIST, at least at the present time.
Journal ArticleDOI
Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification
Mercedes E. Gorre,Mansoor Mohammed,Katharine Ellwood,Nicholas C. Hsu,Ron Paquette,P. Nagesh Rao,Charles L. Sawyers +6 more
TL;DR: It is found that drug resistance is associated with the reactivation of BCR-ABL signal transduction in all cases examined and a strategy for identifying inhibitors of STI-571 resistance is suggested.
Journal ArticleDOI
Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival.
Ronald P. DeMatteo,Jonathan J. Lewis,Denis H. Y. Leung,Salvinder S. Mudan,James M. Woodruff,Murray F. Brennan +5 more
TL;DR: Tumor size predicts disease-specific survival in patients with primary disease who undergo complete gross resection and investigational protocols are indicated to reduce the rate of recurrence after resections and to improve the outcome for patients with GIST.
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