DUPLICATION AND OVEREXPRESSION OF THE MUTANT ALLELE OF THE MET PROTOONCOGENE IN MULTIPLE HEREDITARY PAPILLARY RENAL-CELL TUMORS

Previous karyotyping showed a combined trisomy of chromosome 7 and 17 in sporadic and hereditary papillary renal cell rumours (RCT). A recen t molecular analysis revealed a mutation in the MET tyrosine kinase (c hromosome 7q31) in the germline of four out of seven families with her editary papillary RCT (HPRCT), We have analysed germline cells as well as multiple tumours obtained from HPRCT families and sporadic cases f or alteration of the MET tyrosine kinase and for allelic duplication a t chromosome 7 and 17. We have detected a germ line mutation in the ME T tyrosine kinase in one of the two families with HPRCTs and also foun d the same mutation in the germ line of one patient with clinically re cognized multiple, bilateral papillary RCTs but without family history . The mutant MET allele is consequently duplicated and overexpressed i n tumour cells indicating that duplication of the mutant MET allele is necessary before cells enter the tumorigenic pathway. The lack of ger mline mutation in two members of another HPRT family and duplication o f the same parental allele of chromosome 7 in multiple tumours suggest s that a germ Line event other than mutation of MET tyrosine kinase is involved in the development of these tumours, Duplication of differen t alleles of chromosome 7 in sporadic and of chromosome 17 in both typ es of tumours excludes a germline mutation at these chromosomal sites.