title: Pathologic and molecular heterogeneity in imatinib-stable or imatinib-responsive gastrointestinal stromal tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Narasimhan P
authors.initials: NP
authors.lastname: Agaram
authors.forename: Peter
authors.initials: P
authors.lastname: Besmer
authors.forename: Grace C
authors.initials: GC
authors.lastname: Wong
authors.forename: Tianhua
authors.initials: T
authors.lastname: Guo
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
authors.forename: Diann
authors.initials: D
authors.lastname: DeSantis
authors.forename: Murray F
authors.initials: MF
authors.lastname: Brennan
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.forename: Ronald P
authors.initials: RP
authors.lastname: DeMatteo
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
mesh_terms: D001549:Benzamides; D049109:Cell Proliferation; D016000:Cluster Analysis; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D005091:Exons; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy*; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D008854:Microscopy, Electron; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit