1. ¹Department of Pathology, Stanford University Medical Center, Stanford, CA, USA
2. ²Department of Pathology, Oregon Health and Science University, OHSU Cancer Institute and Portland VA Medical Center, Portland, OR, USA
3. ³Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
4. ⁴Department of Anatomic Pathology, University of Washington Medical Center, Seattle, WA, USA
5. ⁵Department of Surgery, The University of Hong Kong, Hong Kong
6. ⁶Department of Pathology, The University of Hong Kong, Hong Kong
7. ⁷Department of Biochemistry, Stanford University Medical Center, Stanford, CA, USA
8. ⁸Department of Pathology and Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, BC, Canada
9. ⁹Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA
10. ¹⁰Department of Medicine, Oregon Health and Science University, OHSU Cancer Institute and Portland VA Medical Center, Portland, OR, USA

Correspondence: M van de Rijn, Department of Pathology, L-235, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305, USA. E-mail: mrijn@stanford.edu

¹¹These authors contributed equally to this work

Received 22 May 2004; Revised 23 July 2004; Accepted 23 July 2004; Published online 23 August 2004.

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.