<i>PDGFRA</i>
            Activating Mutations in Gastrointestinal Stromal Tumors

Heinrich, Michael C.; Corless, Christopher L.; Duensing, Anette; McGreevey, Laura; Chen, Chang Jie; Joseph, Nora; Singer, Samuel; Griffith, Diana; Haley, Andrea; Town, Ajia; Demetri, George D.; Fletcher, Christopher D.�M.; Fletcher, Jonathan A.

doi:10.1126/science.1079666

Cited by 2,142 publications

(1,589 citation statements)

References 14 publications

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“…Mutation analyses of KIT and PDGFRA genes GIST tumors were analysed for mutations in exons 9, 11, 13 and 17 of the KIT gene and exons 12 and 18 of PDGFRA using a combination of denaturing high-performance liquid chromatography and direct sequencing, as previously described (Heinrich et al, 2003).…”

Section: Rt-pcr Detection Of Fusion Transcriptmentioning

confidence: 99%

MicroRNA expression signature of human sarcomas

et al. 2007

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MicroRNAs (miRNAs) are B22 nucleotide-long noncoding RNAs involved in several biological processes including development, differentiation and proliferation. Recent studies suggest that knowledge of miRNA expression patterns in cancer may have substantial value for diagnostic and prognostic determinations as well as for eventual therapeutic intervention. We performed comprehensive analysis of miRNA expression profiles of 27 sarcomas, 5 normal smooth muscle and 2 normal skeletal muscle tissues using microarray technology and/or small RNA cloning approaches. The miRNA expression profiles are distinct among the tumor types as demonstrated by an unsupervised hierarchical clustering, and unique miRNA expression signatures were identified in each tumor class. Remarkably, the miRNA expression patterns suggested that two of the sarcomas had been misdiagnosed and this was confirmed by reevaluation of the tumors using histopathologic and molecular analyses. Using the cloning approach, we also identified 31 novel miRNAs or other small RNA effectors in the sarcomas and normal skeletal muscle tissues examined. Our data show that different histological types of sarcoma have distinct miRNA expression patterns, reflecting the apparent lineage and differentiation status of the tumors. The identification of unique miRNA signatures in each tumor type may indicate their role in tumorigenesis and may aid in diagnosis of soft tissue sarcomas.

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Section: Rt-pcr Detection Of Fusion Transcriptmentioning

confidence: 99%

MicroRNA expression signature of human sarcomas

et al. 2007

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“…However, radiation and chemotherapy provide a o10% response rate (Dematteo et al, 2000(Dematteo et al, , 2002. Imatinib mesylate (IM), an orally administered selective c-Kit/PDGFR tyrosine kinase inhibitor, abrogates cellular proliferation of GIST cells in culture (Tuveson et al, 2001) and inhibits the constitutively active phosphorylating activity of c-Kit and PDGFR by binding the adenosine 5 0 -trisphosphate (ATP) site preventing the activation of PI-3K and mitogenactivated protein kinase dependent pathways (Heinrich et al, 2003). A randomized trial of GIST patients treated with IM showed that 5% patients achieved a complete response, 47% partial response and 32% stable disease (Verweij et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

et al. 2007

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KIT or a-platelet-derived growth factor receptor (a-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST). Despite excellent responses to imatinib mesylate (IM), patients are relapsing. We developed an IM-resistant GIST cell line (GIST-R) from the IMsensitive GIST882 cell line (GIST-S) by growing these cells in IM. Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance. Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase -AXL -in a 'kinase switch'. Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC). Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL. In GIST-R, AXL is tyrosine phosphorylated and its ligand growtharrest-specific gene 6 is overexpressed implying autocrine activation. The kinase switch is associated with a morphological change from spindle to epithelioid. Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor. MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.

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“…[2][3][4][5] Moreover, recent studies have described activating mutations of plateletderived growth factor receptor-alpha (PDGFRA) at exons 12 and 18 in a minor subset (approximately 5-7%) of GIST. 6 Although GISTs exhibit a spectrum of biologic behavior from benign to malignant, the molecular mechanism of tumor progression has not been fully clarified. Previous studies have reported the prognostic significance of tumor size, mitotic counts, tumor grade, Ki-67 labeling index (LI), 7 KIT mutation type, 4,8,9 p16 inactivation 10 and overexpression of cell-cycle regulators such as cyclin A, cyclin B1 and cdc2.…”

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confidence: 99%

Prognostic significance of angiogenesis in gastrointestinal stromal tumor

et al. 2007

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Angiogenesis is important in the growth and metastasis of various kinds of solid tumors. To investigate the potential role of angiogenesis in gastrointestinal stromal tumor (GIST), an immunohistochemical analysis was performed in 95 cases of GISTs for microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression. MVD was evaluated with immunohistochemical staining for CD31. A high level of MVD was significantly correlated with overexpression of VEGF, tumor location (intestine4stomach), tumor size (Z5 cm), tumor grade (high4intermediate4low grade) (P ¼ o0.0001, 0.0422, 0.0006, 0.0359, respectively). Of the 70 GISTs analyzed, KIT exon 11 mutations were detected in 45 cases (64.3%) and KIT exon 9 mutations in two cases (2.9%). No mutations were found in KIT exons 13 and 17, and platelet-derived growth factor receptor-alpha exons 12 and 18. Interestingly, VEGF expression level was significantly higher in the non-KIT exon 11 mutant group than in the KIT exon 11 mutant group (P ¼ 0.0266). In univariate analysis, tumor grade (high grade), tumor size (Z5 cm), mitotic count (Z5/50 high-power fields), Ki-67 labeling index (Z4.6%), MVD (Z7.0/0.95 mm 2 ) and VEGF expression (high) were significantly associated with a shorter period of disease-free survival (P ¼ o0.0001, 0.0199, 0.0055 0.0027, 0.0028 and 0.0302, respectively). In multivariate analysis, tumor grade and MVD were identified as independent worse prognostic factors (P ¼ 0.0007, 0.0152, respectively). In conclusion, our results suggest that the evaluation of MVD and VEGF expression is useful for predicting the aggressive biologic behavior of GIST, and that angiogenesis associated with VEGF may play an important role, at least in part, in the progression of GIST. Modern Pathology (2007) 20, 529-537.

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PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors

Cited by 2,142 publications

References 14 publications

MicroRNA expression signature of human sarcomas

MicroRNA expression signature of human sarcomas

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

Prognostic significance of angiogenesis in gastrointestinal stromal tumor

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