Spontaneous canine mast cell tumors express tandem duplications in the proto-oncogene c-kit

Spontaneous mast cell tumors (MCT) are the most common malignant neoplasm i n the dog, representing between 7% and 21% of all canine tumors, an inciden ce much higher than that found in humans. These tumors often behave in an a ggressive manner, metastasizing to local lymph nodes, liver, spleen, and bo ne marrow. The proto-oncogene c-kit is known to play a critical role in the development and function of mast cells, Point mutations in the kinase doma in of c-kit leading to tyrosine phosphorylation in the absence of ligand bi nding have been identified in three mastocytoma lines, (P815, RBL, and HMC- 1), and some human patients with various forms of mastocytosis. We now demo nstrate that although c-kit derived from canine MCT did not contain the pre viously described activating point mutations, 5 of the 11 tumors analyzed p ossessed novel mutations consisting of tandem duplications involving exons II and 12, We also show that one such duplication, detected in a canine mas tocytoma cell line, was associated with constitutive phosphorylation of c-k it protein (KIT), suggesting that these mutations may contribute to the dev elopment or progression of canine MCT. (C) 1999 International Society for E xperimental Hematology. Published by Elsevier Science Inc.