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


Authors: 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.
Article Title: Pathologic and molecular heterogeneity in imatinib-stable or imatinib-responsive gastrointestinal stromal tumors
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 ∼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. © 2007 American Association for Cancer Research.
Keywords: adult; clinical article; controlled study; human tissue; treatment outcome; aged; human cell; mutation; exons; histopathology; chemical analysis; cell proliferation; electron microscopy; microscopy, electron; gastrointestinal stromal tumor; imatinib; platelet derived growth factor alpha receptor; stem cell factor; gene overexpression; gastrointestinal stromal tumors; proto-oncogene proteins c-kit; reverse transcription polymerase chain reaction; cluster analysis; genotype; drug effect; drug resistance, neoplasm; pyrimidines; mutational analysis; cell heterogeneity; protein kinase inhibitors; oligonucleotide array sequence analysis; protein-tyrosine kinases; gastrointestinal surgery; piperazines; dna mutational analysis; tumor growth; cell cycle phase; sequence analysis, dna; muscle development
Journal Title: Clinical Cancer Research
Volume: 13
Issue: 1
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2007-01-01
Start Page: 170
End Page: 181
Language: English
DOI: 10.1158/1078-0432.ccr-06-1508
PUBMED: 17200352
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 37" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Murray F Brennan
    756 Brennan
  2. Ronald P DeMatteo
    597 DeMatteo
  3. Narasimhan P Agaram
    117 Agaram
  4. Cristina R Antonescu
    606 Antonescu
  5. Robert Maki
    211 Maki
  6. Samuel Singer
    225 Singer
  7. Nicholas D Socci
    182 Socci
  8. Tianhua Guo
    22 Guo
  9. Peter Besmer
    81 Besmer
  10. Grace C Wong
    11 Wong