Gastrointestinal stromal tumors (GISTs) with KIT and PDGFRA mutations have distinct gene expression profiles

Subbaya Subramanian, Robert B. West, Christopher L. Corless, Wenbin Ou, Brian P. Rubin, Kent Man Chu, Suet Yi Leung, Siu Tsan Yuen, Shirley Zhu, Tina Hernandez-Boussard, Kelli Montgomery, Torsten O. Nielsen, Rajiv M. Patel, John R. Goldblum, Michael C. Heinrich, Jonathan A. Fletcher, Matt Van De Rijn

Research output: Contribution to journalArticlepeer-review

115 Scopus citations

Abstract

Most GISTs require oncogenic activation of the KIT or PDGFRA receptor tyrosine kinase proteins, and the genomic mechanisms of oncogene activation are heterogeneous. Notably, the kinase mutation type correlates with both tumor biology and imatinib response. For example, GISTs with KIT exon 11 mutations are typically gastric and have excellent imatinib response, whereas those with KIT exon 9 mutations generally arise in the small bowel and are less responsive to imatinib. To identify genes that might contribute to these biological differences, we carried out gene expression profiling of 26 GISTs with known KIT and PDGFRA mutational status. Expression differences were then evaluated further by RNA in situ hybridization, immunohistochemistry, and immunoblotting. Unsupervised hierarchical clustering grouped tumors with similar mutations together, but the distinction between the different groups was not absolute. Differentially expressed genes included ezrin, p70S6K, and PKCs, which are known to have key roles in KIT or PDGFRA signaling, and which might therefore contribute to the distinctive clinicopathological features in GISTs with different mutation types. These gene products could serve as highly selective therapeutic targets in GISTs containing the KIT or PDGFRA mutational types with which they are associated.

Original languageEnglish (US)
Pages (from-to)7780-7790
Number of pages11
JournalOncogene
Volume23
Issue number47
DOIs
StatePublished - Oct 14 2004

Keywords

  • GIST
  • Gene expression
  • KIT
  • Microarray
  • Mutations
  • PDGFRA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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