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 in the dog, representing between 7% and 21% of all canine tumors, an incidence much higher than that found in humans. These tumors often behave in an aggressive manner, metastasizing to local lymph nodes, liver, spleen, and bone 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 domain of c-kit leading to tyrosine phosphorylation in the absence of ligand binding have been identified in three mastocytoma lines, (P815, RBL, and HMC-1), and some human patients with various forms of mastocytosis. We now demonstrate that although c-kit derived from canine MCT did not contain the previously described activating point mutations, 5 of the 11 tumors analyzed possessed novel mutations consisting of tandem duplications involving exons 11 and 12. We also show that one such duplication, detected in a canine mastocytoma cell line, was associated with constitutive phosphorylation of c-kit protein (KIT), suggesting that these mutations may contribute to the development or progression of canine MCT.
London
C A
CA
Department of Pathology, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Galli
S J
SJ
Yuuki
T
T
Hu
Z Q
ZQ
Helfand
S C
SC
Geissler
E N
EN
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D004247:DNA / Q000235:genetics; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D005091:Exons / Q000235:genetics; D012515:Mast-Cell Sarcoma / Q000235:genetics / Q000662:veterinary*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017354:Point Mutation; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D019089:Stem Cell Factor / Q000378:metabolism; D020080:Tandem Repeat Sequences; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D019089:Stem Cell Factor; D014443:Tyrosine; D004247:DNA; D019009:Proto-Oncogene Proteins c-kit