Molecular Analysis of c-Kit and PDGFRA in GISTs Diagnosed by EUS

Gomes, Ana; Bardales, Ricardo H.; Milanezi, Fernanda; Reis, Rui; Schmitt, Fernando

doi:10.1309/k1lj-7178-1111-6276

Cited by 30 publications

(39 citation statements)

References 21 publications

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“…Instead, we found the majority of point mutations clustering in the 5 0 and 3 0 regions of exon 11, with a minority of c-kit mutations occurring in exons 9, 13, and 17, as reported in GISTs. The finding of c-kit mutations in exact mutational hotspots as described in GISTs (ie, Leu576Phe, Val643Ala, Asn822Ser) [6][7][8] further adds to the validity of our results.…”

supporting

confidence: 74%

Response to Moskaluk et al

et al. 2010

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supporting

confidence: 74%

Response to Moskaluk et al

et al. 2010

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“…However, no studies have been performed to determine the stability of MT-KIT proteins or to elucidate a mechanism of MT-KIT overexpression. Because it is well known that mutations directly affect the stability of the proteins, it is important to elucidate whether the overexpression of MT-KIT results from the increased stability of mutant proteins or through the assistance of cofactors that are specifically expressed in GISTs (34,35).…”

Section: Discussionmentioning

confidence: 99%

Sustained Mutant KIT Activation in the Golgi Complex Is Mediated by PKC-θ in Gastrointestinal Stromal Tumors

Kim

Yun

Park

et al. 2017

Clinical Cancer Research

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Purpose: Tumorigenesis of gastrointestinal stromal tumors (GIST) is driven by gain-of-function mutations in the KIT gene, which result in overexpression of activated mutant KIT proteins (MT-KIT). However, the mechanism of MT-KIT overexpression is poorly understood.Experimental Design: By protein expression analysis and immunofluorescent microscopic analysis, we determine the stability and localization of MT-KIT in four GIST cell lines with different mutations and HeLa cells transfected with mutant KIT model vectors. We also used 154 human GIST tissues to analyze the relationship between the expression of PKC-q and MT-KITs, and correlations between PKC-q overexpression and clinicopathological parameters.Results: We report that four different MT-KIT proteins are intrinsically less stable than wild-type KIT due to proteasomemediated degradation and abnormally localized to the endoplasmic reticulum (ER) or the Golgi complex. By screening a MT-KITstabilizing factor, we find that PKC-q is strongly and exclusively expressed in GISTs and interacts with intracellular MT-KIT to promote its stabilization by increased retention in the Golgi complex. In addition, Western blotting analysis using 50 GIST samples shows strong correlation between PKC-q and MT-KIT expression (correlation coefficient ¼ 0.682, P < 0.000001). Immunohistochemical analysis using 154 GISTs further demonstrates that PKC-q overexpression significantly correlates with several clinicopathological parameters such as high tumor grade, frequent recurrence/metastasis, and poor patient survival.Conclusions: Our findings suggest that sustained MT-KIT overexpression through PKC-q-mediated stabilization in the Golgi contributes to GIST progression and provides a rationale for anti-PKC-q therapy in GISTs.

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“…This experimental strategy, however, is becoming increasingly popular, with the rationale of delivering TKIs as preoperative cytoreduction agents in order to facilitate surgical resection of initially irresectable or marginally resectable GISTs. In many instances, endoscopic ultrasonographyguided fine-needle aspiration can help in determining c-kit or PDGFRA mutational status, thereby providing useful predictive information regarding the clinical activity of sunitinib and imatinib 95 . Subsequently, [ 18 F]fluorodeoxyglucose positron emission tomography may provide assessment of any therapeutic response to imatinib as early as 8 days after initiation of neoadjuvant TKI treatment 96 .…”

Section: Neoadjuvant Imatinib Mesylate Therapymentioning

confidence: 99%

Surgical management of gastrointestinal stromal tumours

Gervaz

Huber

Morel

2009

British Journal of Surgery

101

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Background: Over the past decade, gastrointestinal stromal tumours (GISTs) have served as a model for the application of tyrosine kinase inhibitors in the treatment of solid neoplasms. Operative and medical management of GISTs is rapidly evolving, but current guidelines appear restricted to basic non-organ-specific recommendations.Methods: A PubMed search was made of the English literature from 1998 to 2008 for references containing the terms 'gastrointestinal stromal tumours' and 'surgery'. This paper reviews the various operative strategies so far reported for GISTs within the digestive tract.Results: Many original procedures tailored to the specific characteristics of these rare sarcomas have been reported. GISTs exhibit distinct features, in particular an absence of metastases within locoregional lymph nodes. Operations requiring extended lymph node dissection, typically designed for adenocarcinomas, such as gastrectomy with extended lymph node dissection, Whipple's procedure and total mesorectum excision, are inappropriate for treating GISTs originating from the stomach, duodenum and rectum respectively.

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Molecular Analysis of c-Kit and PDGFRA in GISTs Diagnosed by EUS

Cited by 30 publications

References 21 publications

Response to Moskaluk et al

Response to Moskaluk et al

Sustained Mutant KIT Activation in the Golgi Complex Is Mediated by PKC-θ in Gastrointestinal Stromal Tumors

Surgical management of gastrointestinal stromal tumours

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