Molecular Comparison of Imatinib-Naïve and Resistant Gastrointestinal Stromal Tumors: Differentially Expressed microRNAs and mRNAs

Cancers

Patrick Schöffski¹  Maria Debiec-Rychter²  Stefan Sleijfer³  PatriciaF. van Kuijk³  ErikA. C. Wiemer³  Azadeh Amirnasr³  CarolineM.M. Gits³  Marcel Smid³  AnneL.M. Vriends³  Raf Sciot⁴  Piotr Rutkowski⁵ 

[1] Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Katholieke Universiteit Leuven, 3000 Leuven, Belgium;Department of Human Genetics, University Hospitals Leuven, Katholieke Universiteit Leuven, 3000 Leuven, Belgium;Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands;Department of Pathology, University Hospitals Leuven, Katholieke Universiteit Leuven, 3000 Leuven, Belgium;Department of Soft Tissue/Bone Sarcoma and Melanoma, Marie Skłodowska-Curie Institute-Oncology Center, 02781 Warsaw, Poland;

关键词: GIST;    miRNA;    mRNA expression;    imatinib;    drug resistance;    gene networks;    IPA pathway analysis;   

DOI  :  10.3390/cancers11060882

来源: DOAJ

【 摘 要 】

Despite the success of imatinib in advanced gastrointestinal stromal tumor (GIST) patients, 50% of the patients experience resistance within two years of treatment underscoring the need to get better insight into the mechanisms conferring imatinib resistance. Here the microRNA and mRNA expression profiles in primary (imatinib-naïve) and imatinib-resistant GIST were examined. Fifty-three GIST samples harboring primary KIT mutations (exon 9; n = 11/exon 11; n = 41/exon 17; n = 1) and comprising imatinib-naïve (IM-n) (n = 33) and imatinib-resistant (IM-r) (n = 20) tumors, were analyzed. The microRNA expression profiles were determined and from a subset (IM-n, n = 14; IM-r, n = 15) the mRNA expression profile was established. Ingenuity pathway analyses were used to unravel biochemical pathways and gene networks in IM-r GIST. Thirty-five differentially expressed miRNAs between IM-n and IM-r GIST samples were identified. Additionally, miRNAs distinguished IM-r samples with and without secondary KIT mutations. Furthermore 352 aberrantly expressed genes were found in IM-r samples. Pathway and network analyses revealed an association of differentially expressed genes with cell cycle progression and cellular proliferation, thereby implicating genes and pathways involved in imatinib resistance in GIST. Differentially expressed miRNAs and mRNAs between IM-n and IM-r GIST were identified. Bioinformatic analyses provided insight into the genes and biochemical pathways involved in imatinib-resistance and highlighted key genes that may be putative treatment targets.

【 授权许可】

Unknown