Abstract
Gastrointestinal stromal tumors（GISTs）are the most common mesenchymal tumors in the human gastrointestinal tract. In the past, basically all of the gastrointestinal mesenchymal tumors had been assumed to be of smooth muscle cell origin. However recent advances in understanding the biology of the tumors demonstrated that most gastrointestinal mesenchymal tumors show differentiation towards gastrointestinal pace maker cells, called interstitial cells of Cajal（ICCs）. We first found that most GISTs expressed KIT, a receptor tyrosine kinase encoded by the protooncogene c-kit, and that approximately 90 ％ of the sporadic GISTs had somatic gain-of-function mutations of the ckit gene. Because both GISTs and ICCs were doublepositive for KIT and CD34, GISTs were considered to originate from ICCs. We also found that about half of the sporadic GISTs without c-kit gene mutations had gain-of-function mutations of platelet-derived growth factor receptor alpha（PDGFRA）gene that encodes another receptor tyrosine kinase. Furthermore, we showed that germline gain-of-function mutations of the c-kit gene resulted in familial and multiple GISTs with diffuse hyperplasia of ICCs as the preexisting lesion. Some knock-in mouse models of familial and multiple GISTs have been genetically created, and may be useful for further investigation of GIST biology. A selective tyrosine kinase inhibitor, imatinib, inhibits constitutive activation of mutated KIT and PDGFRA, and is now being used for metastatic or unresectable GISTs as a molecular target drug. Mutational analyses of c-kit and PDGFRA genes are considered meaningful for prediction of imatinib effect in patients with advanced GISTs.
