title: Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene.
abstract: Hereditary papillary renal carcinoma (HPRC) is a newly recognized inherited disorder characterized by a predisposition to develop multiple bilateral papillary renal carcinomas. Individuals affected with HPRC have been shown to have germ-line mutations in the tyrosine kinase domain of the MET proto-oncogene. We identified a novel mutation in exon 16 of the MET gene in two large North American HPRC families. The H1112R MET mutation segregated with the disease, was not present in 320 normal chromosomes, and caused malignant transformation of NIH 3T3 cells. By examining individuals with the H1112R mutation, we determined the age-dependent penetrance of this mutation and identified additional nonrenal malignancies that occurred in mutation carriers. Affected members of the two families shared the same haplotype within and immediately distal to the MET gene, suggesting a founder effect. The identification of the H1112R mutation will facilitate predictive testing in HPRC and guide future studies of the MET gene in human neoplasia.
authors.affiliation: Intramural Research Support Program, Science Applications International Corporation-Frederick, National Cancer Institute-Frederick Cancer Research & Development Center, Maryland 21702, USA.
authors.forename: L
authors.initials: L
authors.lastname: Schmidt
authors.forename: K
authors.initials: K
authors.lastname: Junker
authors.forename: G
authors.initials: G
authors.lastname: Weirich
authors.forename: G
authors.initials: G
authors.lastname: Glenn
authors.forename: P
authors.initials: P
authors.lastname: Choyke
authors.forename: I
authors.initials: I
authors.lastname: Lubensky
authors.forename: Z
authors.initials: Z
authors.lastname: Zhuang
authors.forename: M
authors.initials: M
authors.lastname: Jeffers
authors.forename: G
authors.initials: G
authors.lastname: Vande Woude
authors.forename: H
authors.initials: H
authors.lastname: Neumann
authors.forename: M
authors.initials: M
authors.lastname: Walther
authors.forename: W M
authors.initials: WM
authors.lastname: Linehan
authors.forename: B
authors.initials: B
authors.lastname: Zbar
mesh_terms: D016475:3T3 Cells; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015197:Carcinogenicity Tests; D002291:Carcinoma, Papillary / Q000235:genetics*; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009378:Neoplasms, Multiple Primary / Q000235:genetics; D009656:North America; D010375:Pedigree; D019683:Penetrance; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D014162:Transfection
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met