Pathologic and molecular heterogeneity in imatinib-stable or imatinib-responsive gastrointestinal stromal tumors

Agaram, N. P., Besmer, P., Wong, G. C., Guo, T., Socci, N. D., Maki, R. G., DeSantis, D., Brennan, M. F., Singer, S., DeMatteo, R. P., Antonescu, C. R. (January 2007) Pathologic and molecular heterogeneity in imatinib-stable or imatinib-responsive gastrointestinal stromal tumors. Clin Cancer Res, 13 (1). pp. 170-81. ISSN 1078-0432 (Print)1078-0432 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/17200352
DOI: 10.1158/1078-0432.CCR-06-1508

Abstract

PURPOSE: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the intestinal tract. Nearly all tumors express KIT protein, and most have an activating mutation in either KIT or PDGFRA. Therapy with selective tyrosine kinase inhibitors achieves a partial response or stable disease in approximately 80% of patients with advanced GIST. However, after an initial clinical response, some patients develop imatinib resistance. Our goal was to investigate the spectrum of pathologic response and molecular alterations in a group of GIST patients, clinically defined as having imatinib-stable/imatinib-responsive lesions, who underwent surgical resection. EXPERIMENTAL DESIGN: Forty-three tumor nodules from 28 patients were available for pathologic and molecular analysis, which included genotyping for primary and secondary KIT/PDGFRA-mutations, cell cycle alterations, and biochemical activation status of KIT and downstream targets. The transcriptional changes of a subset of these tumors were compared with a group of imatinib-naive GISTs on a U133A Affymetrix expression platform. RESULTS: The histologic response did not correlate with imatinib therapy duration or with proliferative activity. Second-site KIT mutation was identified in only one tumor nodule. Activation of KIT and downstream targets was consistent in all tumors analyzed. Ultrastructurally, a subset of tumors showed a smooth muscle phenotype, which correlated with overexpression of genes involved in muscle differentiation and function. CONCLUSIONS: The histologic response to imatinib is heterogeneous and does not correlate well with clinical response. Second-site KIT mutations are rare in imatinib-responsive GISTs compared with imatinib-resistant tumors. The gene signature of imatinib-response in GISTs showed alterations of cell cycle control as well as up-regulation of genes involved in muscle differentiation and function.

Item Type: Paper
Uncontrolled Keywords: Benzamides Cell Proliferation Cluster Analysis DNA Mutational Analysis Drug Resistance, Neoplasm Exons Gastrointestinal Stromal Tumors/*drug therapy Genotype Humans Imatinib Mesylate Microscopy, Electron Mutation Oligonucleotide Array Sequence Analysis Piperazines/*pharmacology Protein Kinase Inhibitors/*pharmacology Protein-Tyrosine Kinases/antagonists & inhibitors Proto-Oncogene Proteins c-kit/*genetics Pyrimidines/*pharmacology Sequence Analysis, DNA Treatment Outcome
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell proliferation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons
diseases & disorders > cancer > cancer types > gastrointestinal stromal tumors
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
CSHL Authors:
Communities: CSHL labs > Maki lab
Depositing User: Matt Covey
Date: 1 January 2007
Date Deposited: 26 Oct 2016 20:02
Last Modified: 26 Oct 2016 20:02
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33668

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