Novel mutations of the MET proto-oncogene in papillary renal carcinomas

Hereditary papillary renal carcinoma (HPRC) is characterized by multiple, b ilateral papillary renal carcinomas. Previously, we demonstrated missense m utations in the tyrosine kinase domain of the MET proto-oncogene in HPRC an d a subset of sporadic papillary renal carcinoma In this study, me screened a large panel of sporadic papillary renal carcinomas and various solid tum ors for mutations in the MET protooncogene, Summarizing these and previous results, mutations of the MET proto-oncogene were detected in 17/129 sporad ic papillary renal carcinomas but not in other solid tumors. We detected fi ve novel: missense mutations; three of five mutations were located in the A TP-binding region of the tyrosine kinase domain of MET. One novel mutation in MET, V1110I, was located at a codon homologous to an activating mutation in the c-erbB proto-oncogene, These mutations caused constitutive phosphor ylation of MET when transfected into NIH3T3 cells. Molecular modeling studi es suggest that these activating mutations interfere with the intrasteric m echanism of tyrosine kinase autoinhibition and facilitate transition to the active form of the MET kinase, The low frequency of MET mutations in nonin herited papillary renal carcinomas (PRC) suggests that noninherited PRC may develop by a different mechanism than hereditary papillary renal carcinoma .