c-kit Mutations in Gastrointestinal Stromal Tumors Occur Preferentially in the Spindle Rather Than in the Epithelioid Cell Variant

Wardelmann, Eva; Neidt, Iris; Bierhoff, E.; Speidel, Nicola; Manegold, Christoph; Fischer, Hans‐Peter; Pfeifer, U; Pietsch, Torsten

doi:10.1038/modpathol.3880504

Cited by 112 publications

(86 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5 In addition, the prevalence of the spindle-cell type of GISTs might influence the low frequency of PDGFRA gene mutation in the current study, because, in general, PDGFRA mutation is more frequently present in epithelioid-cell type GISTs than in spindle-cell type GISTs (most of our cases were spindle-cell type). 41 In conclusion, we found that MVD was correlated with both VEGF overexpression and worse prognosis in GISTs. Our results suggest that angiogenesis measured as MVD 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.…”

Section: Factorsmentioning

confidence: 57%

Prognostic significance of angiogenesis in gastrointestinal stromal tumor

et al. 2007

View full text Add to dashboard Cite

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.

show abstract

Section: Factorsmentioning

confidence: 57%

Prognostic significance of angiogenesis in gastrointestinal stromal tumor

et al. 2007

View full text Add to dashboard Cite

show abstract

“…9,10,18 Activating mutations within the KIT gene were detected in 57-92% of GISTs in earlier reports. [9][10][11][12][13]16 The frequency of KIT mutations in our series was apparently lower in epithelioid than in mixed and spindle type GISTs. Previous reports have already suggested that the frequency of KIT mutations in epithelioid GISTs may be lower than in spindle cell variants.…”

Section: Discussionmentioning

confidence: 98%

“…Previous reports have already suggested that the frequency of KIT mutations in epithelioid GISTs may be lower than in spindle cell variants. Accordingly, Wardelmann et al 16 reported no KIT mutations in seven GISTs with an epithelioid component, while all 21 GISTs with detectable KIT mutations displayed a spindle cell phenotype. This finding was supported by a more recent study 13 that included 19 epithelioid GISTs and only six of which harbored KIT mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have suggested that the frequency of KIT mutations in epithelioid type GISTs may be lower than in tumors of spindle cell type. 13,16 Additionally, all primary GISTs with activating mutations of PDGFRA reported by Hirota et al 15 originated from the stomach. It is unclear, however, whether these GISTs carrying PDGFRA mutant isoforms were associated with any specific GIST morphological variant.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Differential expression of KIT/PDGFRA mutant isoforms in epithelioid and mixed variants of gastrointestinal stromal tumors depends predominantly on the tumor site

et al. 2004

View full text Add to dashboard Cite

Gastrointestinal stromal tumors (GISTs) form a distinctive group of mesenchymal neoplasms, showing differentiation towards the interstitial cells of Cajal. Morphologically, GISTs vary from cellular spindle cell tumors to epithelioid or mixed, epithelioid and spindle cell variants. The genotypic features underlying the morphologic differences of GISTs with vs without epithelioid components are not well defined. Acquisition of activating mutations in KIT and PDGFRA has been reported as alternative oncogenic events in the pathogenesis of GISTs. In this study, a comprehensive KIT and PDGFRA mutational analysis was performed in a group of 28 epithelioid/mixed type tumors, in order to explore whether a specific KIT/PDGFRA mutational status segregates these neoplasms from spindle cell variant GISTs. All GISTs were primary neoplasms, 16 (57.1%) originated from the stomach and 12 (42.8%) from other locations. Histomorphologically, 14 GISTs showed an epithelioid and 14 a mixed cell type pattern. Mutational analysis included KIT exons 9, 11, 13, and 17, and PDGFRA exons 12 and 18 prescreening by denaturing high-performance liquid chromatography, followed by direct sequencing. Activating mutations of KIT were found in 14 (50%) GISTs, the majority being within exon 11 (n ¼ 11; 39.2%), and the other comprised exon 9 AY 502-503 duplications (n ¼ 2; 7.2%) and exon 17 Lys-Aln 822 missense mutations (n ¼ 1; 3.6%). Most of the KIT mutant tumors (n ¼ 11; 78.6%) originated from nongastric sites. Seven (25.0%) GISTs with no detectable KIT mutations demonstrated PDGFRA mutant isoforms, carrying either D842 V mutations (n ¼ 5) or exon 18 deletions (n ¼ 2). All GISTs harboring PDGFRA mutant isoforms originated from the stomach. In seven tumors, no detectable mutations were found; all but one of nonmutant tumors initiated from the stomach and exhibited an epithelioid morphology. These findings indicate that the mutational status of epithelioid/mixed GISTs associates with the anatomical site of the tumor.

show abstract

“…The prognostic and therapeutic significance of KIT mutations is somewhat contradictory (Ernst et al, 1998;Lasota et al, 1999;Moskaluk et al, 1999;Taniguchi et al, 1999;Lasota et al, 2000;Hirota et al, 2001;Wardelmann et al, 2002;Koay et al, 2005). Therefore, it appears that new molecular indicators of prognostication are needed.…”

mentioning

confidence: 99%

Tissue microarrays characterise the clinical significance of a VEGF-A protein expression signature in gastrointestinal stromal tumours

et al. 2007

View full text Add to dashboard Cite

show abstract

c-kit Mutations in Gastrointestinal Stromal Tumors Occur Preferentially in the Spindle Rather Than in the Epithelioid Cell Variant

Abstract: Gastrointestinal stromal tumors (GISTs) coexpress CD34 and the Kit tyrosine-kinase receptor (CD117). A subset of GISTs carry gain-of-function mutations

Cited by 112 publications

References 25 publications

Prognostic significance of angiogenesis in gastrointestinal stromal tumor

Prognostic significance of angiogenesis in gastrointestinal stromal tumor

Differential expression of KIT/PDGFRA mutant isoforms in epithelioid and mixed variants of gastrointestinal stromal tumors depends predominantly on the tumor site

Tissue microarrays characterise the clinical significance of a VEGF-A protein expression signature in gastrointestinal stromal tumours

Contact Info

Product

Resources

About