KIT Exon (kit + exon)

Distribution by Scientific Domains


Selected Abstracts


Hereditary gastrointestinal stromal tumors sharing the KIT Exon 17 germline mutation p.Asp820Tyr develop through different cytogenetic progression pathways

GENES, CHROMOSOMES AND CANCER, Issue 2 2010
Isabel Veiga
Hereditary gastrointestinal stromal tumor (GIST) syndrome is a rare autosomal dominant genetic disorder originated by germline mutations in the KIT or PDGFRA genes. We report the third family with hereditary predisposition to GIST due to the KIT Exon 17 germline mutation p.Asp820Tyr and characterize the cytogenetic progression pathways followed by different GIST sharing the same primary genetic event, using a combination of chromosome banding, comparative genomic hybridization (CGH), and fluorescence in situ hybridization (FISH) analyses. The missense mutation p.Asp820Tyr was detected in the proband's rectal and gastric GIST, as well as in his aunt's GIST epiplon metastasis. The mutation p.Asp820Tyr was subsequently also found in the proband's peripheral blood DNA, as well as in that of 4 of 10 relatives thus far analyzed. CGH analysis revealed loss of 14q and 15q in the proband's gastric lesion, whereas FISH analysis of the proband's rectal GIST did not detect loss of 14q and 15q, but instead loss of 4q and 22q and gain of 20q, indicating that the two tumors were independent GIST. Chromosome banding and CGH analyses of the aunt's GIST epiplon metastasis revealed multiple cytogenetic alterations, including 1p loss, but none in common with the two proband's GIST. We conclude that, although the patients share the same KIT Exon 17 germline mutation, the multiple GIST analyzed followed different pathogenetic progression pathways, each of which did not significantly differ from what has been described in sporadic GIST. 2009 Wiley-Liss, Inc. [source]


Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours

HISTOPATHOLOGY, Issue 3 2008
J Lasota
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Despite clinicopathological differences, GISTs share oncogenic KIT or platelet-derived growth factor-alpha (PDGFRA) mutations. Imatinib, KIT and PDGFRA inhibitor, has been successfully used in the treatment of metastatic GISTs. There are primary KIT or PDGFRA mutations diagnosed before imatinib treatment, linked to GIST pathogenesis, and secondary mutations detected during treatment, causing drug resistance. KIT exon 11 mutations are the most common. Gastric GISTs with exon 11 deletions are more aggressive than those with substitutions. KIT exon 11 mutants respond well to imatinib. Less common KIT exon 9 Ala502_Tyr503dup mutants occur predominantly in intestinal GISTs and are less sensitive to imatinib. An Asp842Val substitution in exon 18 is the most common PDGFRA mutation. GISTs with such mutation are resistant to imatinib. PDGFRA mutations are associated with gastric GISTs, epithelioid morphology and a less malignant course of disease. GISTs in neurofibromatosis 1, Carney triad and paediatric tumours generally lack KIT and PDGFRA mutations. Secondary KIT mutations affect exons 13,17. GISTs with secondary mutations in exon 13 and 14 are sensitive to sunitinib, another tyrosine kinase inhibitor. KIT and PDGFRA genotyping is important for GIST diagnosis and assessment of sensitivity to tyrosine kinase inhibitors. [source]


Increased KIT signalling with up-regulation of cyclin D correlates to accelerated proliferation and shorter disease-free survival in gastrointestinal stromal tumours (GISTs) with KIT exon 11 deletions,

THE JOURNAL OF PATHOLOGY, Issue 2 2008
F Haller
Abstract Gastrointestinal stromal tumours (GISTs) with deletions in KIT exon 11 are characterized by higher proliferation rates and shorter disease-free survival times, compared to GISTs with KIT exon 11 point mutations. Up-regulation of cyclin D is a crucial event for entry into the G1 phase of the cell cycle, and links mitogenic signalling to cell proliferation. Signalling from activated KIT to cyclin D is directed through the RAS/RAF/ERK, PI3K/AKT/mTOR/EIF4E, and JAK/STATs cascades. ERK and STATs initiate mRNA transcription of cyclin D, whereas EIF4E activation leads to increased translation efficiency and reduced degradation of cyclin D protein. The aim of the current study was to analyse the mRNA and protein expression as well as protein phosphorylation of central hubs of these signalling cascades in primary GISTs, to evaluate whether tumours with KIT exon 11 deletions and point mutations differently utilize these pathways. GISTs with KIT exon 11 deletions had significantly higher mitotic counts, higher proliferation rates, and shorter disease-free survival times. In line with this, they had significantly higher expression of cyclin D on the mRNA and protein level. Furthermore, there was a significantly higher amount of phosphorylated ERK1/2, and a higher protein amount of STAT3, mTOR, and EIF4E. PI3K and phosphorylated AKT were also up-regulated, but this was not significant. Ultimately, GISTs with KIT exon 11 deletions had significantly higher phosphorylation of the central negative cell-cycle regulator RB. Phosphorylation of RB is accomplished by activated cyclin D/CDK4/6 complex, and marks a central event in the release of the cell cycle. Altogether, these observations suggest increased KIT signalling with up-regulation of cyclin D as the basis for the unfavourable clinical course in GISTs with KIT exon 11 deletions. Copyright 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source]


Mutations in gastrointestinal stromal tumors , a population-based study from Northern Norway,

APMIS, Issue 4 2007
SONJA E. STEIGEN
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. This tumor typically expresses KIT, and has KIT or PDGFRA activating mutation. In this study we evaluated 89 GISTs diagnosed in Northern Norway during a 30-year period. KIT exons 8, 9, 11, 13, and 17 were analyzed by PCR amplification and direct sequencing. Subsequently PDGRA exons 12, 14, and 18 were evaluated in KIT wild-type cases. KIT mutations were found in 66 cases (75%), and PDGFRA mutations in 9 cases (10%). Most common were KIT exon 11 mutations, with 58 cases. Tumors with Kit exon 11 point mutations had a significantly better prognosis than those with deletions. There were five KIT exon 9 duplications, three exon 13 point mutations, and one point mutation in exon 17. There were nine PDGFGRA mutations: seven in exon 18 and two in exon 12. All but one PDGFRA mutant GISTs were gastric tumors with epithelioid morphology, and these tumors were on average smaller than those with KIT mutations. KIT and PDGFRA wild type was found in 15% of cases. Analysis of KIT and PDGFRA mutations is of significance for treatment with tyrosine kinase inhibitors, and may also have value when assessing the biological potential of GIST. [source]


Amplification of genes encoding KIT, PDGFR, and VEGFR2 receptor tyrosine kinases is frequent in glioblastoma multiforme

THE JOURNAL OF PATHOLOGY, Issue 2 2005
Heikki Joensuu
Abstract KIT, platelet-derived growth factor receptors (PDGFRs) and vascular endothelial growth factor receptors (VEGFRs) are important clinical targets for tyrosine kinase inhibitors. The frequency of KIT and VEGFR2 amplification in glioblastomas is not known, and few data are available in any other human tumour type. We investigated 43 primary glioblastomas for KIT, VEGFR2, PDGFRA and EGFR amplification using fluorescence in situ hybridization. KIT was amplified in 47% and VEGFR2 in 39% of the glioblastomas, respectively, and PDGFRA in 29%. Thirty-five (81%) of the tumours had either KIT or EGFR amplification. KIT, PDGFRA and VEGFR2 amplifications were strongly associated (p < 0.0001 for each pairwise comparison), suggesting co-amplification, whereas no significant association was found with EGFR amplification. The four secondary glioblastomas arising from pre-existing lower grade astrocytic tumours investigated had KIT amplification but none had EGFR amplification. No mutations were detected with denaturing high-performance liquid chromatography in KIT exons 9, 11, 13 or 17, PDGFRA exons 12 and 18, or EGFR exons 18, 19 or 21. Glioblastomas with KIT, PDGFR or VEGFR2 amplification were associated with similar outcome to other glioblastomas. We conclude that KIT, PDGFRA and VEGFR2 are commonly amplified in primary glioblastoma and that they may also be amplified in secondary glioblastoma. Amplified kinases may be potential targets for tyrosine kinase inhibitor therapy. Copyright 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source]


Mutations in gastrointestinal stromal tumors , a population-based study from Northern Norway,

APMIS, Issue 4 2007
SONJA E. STEIGEN
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. This tumor typically expresses KIT, and has KIT or PDGFRA activating mutation. In this study we evaluated 89 GISTs diagnosed in Northern Norway during a 30-year period. KIT exons 8, 9, 11, 13, and 17 were analyzed by PCR amplification and direct sequencing. Subsequently PDGRA exons 12, 14, and 18 were evaluated in KIT wild-type cases. KIT mutations were found in 66 cases (75%), and PDGFRA mutations in 9 cases (10%). Most common were KIT exon 11 mutations, with 58 cases. Tumors with Kit exon 11 point mutations had a significantly better prognosis than those with deletions. There were five KIT exon 9 duplications, three exon 13 point mutations, and one point mutation in exon 17. There were nine PDGFGRA mutations: seven in exon 18 and two in exon 12. All but one PDGFRA mutant GISTs were gastric tumors with epithelioid morphology, and these tumors were on average smaller than those with KIT mutations. KIT and PDGFRA wild type was found in 15% of cases. Analysis of KIT and PDGFRA mutations is of significance for treatment with tyrosine kinase inhibitors, and may also have value when assessing the biological potential of GIST. [source]