Abstract
Simple SummaryFor intestinal localized high-risk gastrointestinal stromal tumors (GIST) patients’ new molecular biomarkers are urgently needed for a more accurate prognosis. In our study, miRNA profiling analyses was planned to explore new molecular biomarkers with potential prognostic role in this clinical context. Our data, revealed that 39 microRNAs (miRNAs) were significantly deregulated when comparing patients with disease relapsed versus non-relapsed cases. The underexpression of a specific miRNA let-7e and the overexpression of 4 of its target genes (ACVR1B, CASP3, COL3A1 and COL5A2) correlated significantly with worse relapse-free survival. Overall, our results suggest that miRNA profiling is a potential molecular tool useful for a more accurate prognosis for intestinal localized high-risk GIST patients.MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level, and they have been described as being associated with tumor prognosis. Here, miRNA profiling was planned to explore new molecular prognostic biomarkers in localized intestinal high-risk GIST. Paraffin tumor blocks of 14 and 86 patients were used in the discovery and expansion sets, respectively. GeneChip miRNA v3.0 was employed to identify the miRNAs differentially expressed between relapsed and non-relapsed patient samples, which were validated in the expansion set, by qRT-PCR. RT2 Profiler PCR Array was used for the screening of let-7e targets. Expression levels were correlated with relapse-free survival and overall survival. In the discovery set, 39 miRNAs were significantly deregulated, let-7e and miR-550 being the most underexpressed and overexpressed miRNAs in the relapsed group, respectively. In the expansion set, the underexpression of let-7e or the overexpression of 4 of its target genes (ACVR1B, CASP3, COL3A1, and COL5A2) were statistically associated with worse relapse-free survival. The expression of let-7e and 4 of its target genes are potential prognostic biomarkers in high-risk localized intestinal GIST. The expression of these genes is a potential molecular tool useful for a more accurate prognosis in this subset of GIST patients.
Highlights
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract
Our results suggest that miRNA profiling is a potential molecular tool useful for a more accurate prognosis for intestinal localized high-risk GIST patients
The prognostic value of both, in let-7e and miR-550 wasavalidated by qRT-PCR, confirming its the samples according to its prognosis
Summary
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs represent a paradigmatic solid-tumor model for targeted therapy with 3 tyrosine-kinase inhibitors (TKI) registered for first [2], second [3] and third [4] lines in advanced disease and adjuvant Imatinib for high-risk localized GIST [5]. Despite this enormous therapeutic investigation on molecular targeted therapy in this entity, the risk classification for localized GIST patients still relies on clinical-pathological features such as mitotic count, size tumor location, and tumor rupture [6]. With the aim of exploring new molecular biomarkers with a potential prognostic role in localized GIST, a miRNA profiling analysis was planned in the context of intestinal localized high-risk GIST patients
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