Abstract 4345: Molecular comparison of imatinib-naïve and resistant gastrointestinal stromal tumors: Differentially expressed microRNAs and mRNAs

Abstract

Abstract Background and aim: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the gastrointestinal tract. Gain-of-function mutations in KIT or, less frequently, PDGFRA underlie the pathogenesis of the majority of these tumors. The introduction of imatinib mesylate, a selective tyrosine kinase inhibitor, has dramatically improved the outcome for GIST patients. However, half of the advanced patients treated with imatinib eventually progress and acquire resistance within two years of treatment, underscoring the need to get better insight into the resistance mechanisms. In this context we examined the miRNA and mRNA expression profiles in primary (imatinib-naïve) and imatinib resistant GIST samples. Material and Methods: Fifty-three frozen GIST samples derived from various anatomical sites (small intestine, stomach, colon) harboring a KIT mutation including exon 9 (n=11), exon 11 (n=41) and exon 17 (n=1), were analyzed. Total RNA was isolated from imatinib naïve (IM-n; n=33) and resistant (IM-r; n=20) tumors. The resistant tumors bearing secondary mutations in exon 13 (n=3), exon 17 (n=6) or no secondary mutations (n=11). The miRNA expression profiles were determined using LNA™ oligonucleotide arrays (Exiqon) capable of detecting 725 human miRNAs. Furthermore, from a subset of samples (IM-n; n=14; IM-r; n=15) the mRNA expression profile was established using Affymetrix U133A oligonucleotide arrays. Using the mRNA expression data and the Biocarta and KEGG databases, global testing identified a number of biochemical pathways containing genes that are differentially expressed between the primary and progressive tumors. Results: Thirty-five differentially expressed miRNAs (P<0.009, FDR<20%) between IM-n and IM-r GIST samples were identified. MiR-30c, miR-181a and miR-144 were among the most significantly different, with p values of 0.006, 0.006 and 0.003, respectively. Analysis of the mRNA data has revealed the up-regulation of genes (P <0002, FDR<30%) involved in cell cycle, DNA replication and cancer related pathways (i.e. proliferation, genomic instability, resistance to chemotherapy, evading apoptosis, etc.) in IM-r samples. To further elucidate the possible involvement of the deregulated miRNAs in the regulation of the indicated genes, the most significantly differentially expressed genes were correlated to miRNA expression. Negative correlations indicate miRNA mediated gene regulation, and were further examined in target prediction programs. Conclusion: A molecular comparison between primary, IM-n and IM-r GIST samples revealed significant differentially expressed miRNAs and mRNAs. Bioinformatic analyses provided insight into biochemical pathways, and their putative regulation by miRNAs, that may contribute to imatinib resistance as observed in GIST patients. Citation Format: Azadeh Amirnasr, Caroline M. Gits, Patricia F. Kuijk, Marcel Smid, Maria Debiec-Rychter, Stefan Sleijfer, Erik A. Wiemer. Molecular comparison of imatinib-naïve and resistant gastrointestinal stromal tumors: Differentially expressed microRNAs and mRNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4345.