Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancies found in the gastrointestinal tract. At a molecular level, most GISTs are characterized by gain-of-function mutations in V-Kit Hardy–Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog (KIT) and Platelet Derived Growth Factor Receptor Alpha (PDGFRA), leading to constitutive activated signaling through these receptor tyrosine kinases, which drive GIST pathogenesis. In addition to surgery, treatment with the tyrosine kinase inhibitor imatinib forms the mainstay of GIST treatment, particularly in the advanced setting. Nevertheless, the majority of GISTs develop imatinib resistance. Biomarkers that indicate metastasis, drug resistance and disease progression early on could be of great clinical value. Likewise, novel treatment strategies that overcome resistance mechanisms are equally needed. Non-coding RNAs, particularly microRNAs, can be employed as diagnostic, prognostic or predictive biomarkers and have therapeutic potential. Here we review which non-coding RNAs are deregulated in GISTs, whether they can be linked to specific clinicopathological features and discuss how they can be used to improve the clinical management of GISTs.
Highlights
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancies found in the gastrointestinal tract
The fact of GIST originating from interstitial cells of Cajal (ICC) is exemplified by shared immune-phenotypical features such as the expression of V-Kit Hardy–Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog (KIT) (CD117) [5,6], anoctamin 1 (ANO1/DOG1) [7] and ETV1 [8], which are currently used as diagnostic biomarkers for GIST
Platelet Derived Growth Factor Receptor Alpha (PDGFRA) D842V mutants are resistant to imatinib [27,28], the same as wild-type GISTs (WT-GIST) and GISTs with mutations in genes other than KIT and PDGFRA that display insensitivity to imatinib and other tyrosine kinase inhibitors [29]
Summary
Gastrointestinal stromal tumors (GISTs) are rare tumors of mesenchymal origin from the gastrointestinal (GI) tract with an estimated annual incidence of 10–20 per 1,000,000 in the population [1,2,3]. They can be found anywhere along the GI tract, but occur most commonly in the stomach (60–70%) and small intestine (20–30%) [4]. The specific mutations in KIT and PDGFRA, with the exception of PDGFRA D842V, make GISTs amenable to treatment with the tyrosine kinase inhibitor imatinib This drug selectively inhibits the kinase activity of KIT and PDGFRA through competitive binding at the ATP binding site of these enzymes [13,14,15]. In these so-called wild-type GISTs (WT-GIST), other mutated genes such as NF1, BRAF and succinate dehydrogenase subunits (SDHB, SDHC, SDHD) can drive tumorigenesis [16,17,18,19,20]
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