Abstract
Purpose
Surgical removal or treatment with Imatinib mesylate (STI-571/Gleevec) is shown to be highly effective in gastrointestinal stromal tumors (GISTs). However, it is unclear the understanding of the molecular basis in GISTs according to its malignant potential. The aim of this study was therefore to determine the gene expression profiles according to GISTs risk progresses.
Results
In this study, we performed a cDNA microarray with 30 human GIST tissues using the Mac Array-Express 10K chip (10,800 genes), and compared their gene expression profiles among low (n = 10), intermediate (n = 8), and high-risk groups (n = 12) according to NIH consensus criteria. A total of 181 genes were identified to be expressed differentially according to GISTs risk category. After clustering by self-organizing maps, the expression profiles of 32 genes sequentially increased as the tumor risk increased, and those of 37 genes sequentially decreased as the tumor risk increased. Identified targets have been cross referenced against their involvements in different cellular pathways, according to GenMAPP, KEGG, and BioCarta. In pathway-enrichment analysis, eight up-regulated pathways and ten down-regulated pathways were significantly enriched.
Conclusions
Our results showed a remarkably distinct and uniform expression pattern in GISTs progression. Moreover, the expression profiling of GISTs may be used as a basic reference to better understand the molecular basis of GISTs tumorigenesis and to identify a novel target molecule for replacing KIT and PDGFRA for a complementary diagnosis and effective curative treatments.
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References
Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002;33:459–465.
Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (gipact): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of cajal. Am J Pathol. 1998;152:1259–1269.
Miettinen M, Lasota J. Gastrointestinal stromal tumors—definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch. 2001;438:1–12.
Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22:3813–3825.
Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031–1037.
Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001;344:1052–1056.
van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet. 2001;358:1421–1423.
Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-KIT in human gastrointestinal stromal tumors. Science. 1998;279:577–580.
Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708–710.
Debiec-Rychter M, Dumez H, Judson I, et al. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2004;40:689–695.
Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472–480.
Verweij J, van Oosterom A, Blay JY, et al. Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer. 2003;39:2006–2011.
Chen LL, Trent JC, Wu EF, et al. A missense mutation in kit kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors. Cancer Res. 2004;64:5913–5919.
Eberwine J. Amplification of mRNA populations using aRNA generated from immobilized oligo(dT)-T7 primed cDNA. Biotechniques. 1996;20:584–591.
Huber W, von Heydebreck A, Sultmann H, Poustka A, Vingron M. Variance stabilization applied to microarray data calibration and to the quantification of differential expression. Bioinformatics. 2002;18(Suppl 1):S96–104.
Yang YH, Dudoit S, Luu P, et al. Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. Nucleic Acids Res. 2002;30:e15.
Kohonen T. Self-organizing maps. Berlin Heidelberg New York: Springer; 1995.
Antonescu CR, Viale A, Sarran L, et al. Gene expression in gastrointestinal stromal tumors is distinguished by kit genotype and anatomic site. Clin Cancer Res. 2004;10:3282–3290.
Subramanian S, West RB, Corless CL, et al. Gastrointestinal stromal tumors (GISTs) with kit and PDGFRA mutations have distinct gene expression profiles. Oncogene. 2004;23:7780–7790.
Nielsen TO, West RB, Linn SC, et al. Molecular characterisation of soft tissue tumours: a gene expression study. Lancet. 2002;359:1301–1307.
Acknowledgments
This study was supported by the Cancer Research Institute, Seoul National University (CRI-04-4).
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Hur, K., Lee, HJ., Woo, J.H. et al. Gene Expression Profiling of Human Gastrointestinal Stromal Tumors According to Its Malignant Potential. Dig Dis Sci 55, 2561–2567 (2010). https://doi.org/10.1007/s10620-009-1061-4
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DOI: https://doi.org/10.1007/s10620-009-1061-4