Interstitial cells of Cajal do not harbor c-kit or PDGFRA gene mutations in patients with sporadic gastrointestinal stromal tumors

Background: Gastrointestinal stromal tumors (GISTs) are believed to originate from the interstitial cells of Cajal (ICCs) or from the precursors of ICCs. Most GISTs show an activating mutation in either the c-kit or platelet-derived growth factor receptor α (PDGFRA) gene that results in a constitutive, ligand-independent activation of receptor tyrosine kinases. These gene mutations may play an important role in transforming a GIST progenitor cell into a tumor cell during the early phase of GIST tumorigenesis. However, the precise mechanism of the tumorigenesis is not known. Methods: We examined ten patients with sporadic GIST for mutations in the tumor and its adjacent ICC cells, and compared the mutational status of ICC cells with that of the GIST cells in each patient. All cases were screened for mutations in the c-kit gene (exons 9, 11, 13, and 17) and in the PDGFRA gene (exons 12 and 18). Samples were limited to GIST cases from the small intestine, where ICCs were present in bundles and were considered suitable for isolation by laser capture microdissection. Results: Of the ten tumors screened, eight had mutations in the c-kit gene (all in exon 11) and two were wild-type, whereas none of the ICCs exhibited mutations in these genes. Conclusions: Our results suggest that ICCs adjacent to overt GISTs did not have mutations in the c-kit or PDGFRA genes, and overt GISTs may develop after the local and sporadic acquisition of these gene mutations, together with additional events.