GERMLINE AND SOMATIC MUTATIONS IN THE TYROSINE KINASE DOMAIN OF THE MET PROTOONCOGENE IN PAPILLARY RENAL CARCINOMAS

Hereditary papillary renal carcinoma (HPRC) is a recently recognized f orm of inherited kidney cancer characterized by a predisposition to de velop multiple, bilateral papillary renal tumours(1-4). The pattern of inheritance of HPRC is consistent with autosomal dominant transmissio n with reduced penetrance. HPRC is histologically and genetically dist inct from two other causes of inherited renal carcinoma, von Hippel-Li ndau disease (VHL) and the chromosome translocation (3;8)(5-6). Malign ant papillary renal carcinomas are characterized by trisomy of chromos omes 7, 16 and 17, and in men, by loss of the Y chromosome(7), Inherit ed and sporadic clear cell renal carcinomas are characterized by inact ivation of both copies of the VHL gene by mutation, and/or by hypermet hylation(8-11). We found that the HPRC gene was located at chromosome 7q31.1-34 in a 27-centimorgan (cM) interval between D7S496 and D7S1837 . We identified missense mutations located in the tyrosine kinase doma in of the MET gene in the germline of affected members of HPRC familie s and in a subset of sporadic Family: papillary renal carcinomas. Thre e mutations in the MET gene are located in codons that are homologous to those in c-kit and RET, proto-oncogenes that are targets of natural ly-occurring mutations. The results suggest that missense mutations lo cated in the MET proto-oncogene lead to constitutive activation of the MET protein and papillary renal carcinomas.