title: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas.
abstract: Hereditary papillary renal carcinoma (HPRC) is a recently recognized form of inherited kidney cancer characterized by a predisposition to develop multiple, bilateral papillary renal tumours. The pattern of inheritance of HPRC is consistent with autosomal dominant transmission with reduced penetrance. HPRC is histologically and genetically distinct from two other causes of inherited renal carcinoma, von Hippel-Lindau disease (VHL) and the chromosome translocation (3;8). Malignant papillary renal carcinomas are characterized by trisomy of chromosomes 7, 16 and 17, and in men, by loss of the Y chromosome. Inherited and sporadic clear cell renal carcinomas are characterized by inactivation of both copies of the VHL gene by mutation, and/or by hypermethylation. 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 domain of the MET gene in the germline of affected members of HPRC families and in a subset of sporadic papillary renal carcinomas. Three 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 naturally-occurring mutations. The results suggest that missense mutations located in the MET proto-oncogene lead to constitutive activation of the MET protein and papillary renal carcinomas.
authors.affiliation: Intramural Research Support Program, SAIC Frederick, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Schmidt
authors.forename: F M
authors.initials: FM
authors.lastname: Duh
authors.forename: F
authors.initials: F
authors.lastname: Chen
authors.forename: T
authors.initials: T
authors.lastname: Kishida
authors.forename: G
authors.initials: G
authors.lastname: Glenn
authors.forename: P
authors.initials: P
authors.lastname: Choyke
authors.forename: S W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Z
authors.initials: Z
authors.lastname: Zhuang
authors.forename: I
authors.initials: I
authors.lastname: Lubensky
authors.forename: M
authors.initials: M
authors.lastname: Dean
authors.forename: R
authors.initials: R
authors.lastname: Allikmets
authors.forename: A
authors.initials: A
authors.lastname: Chidambaram
authors.forename: U R
authors.initials: UR
authors.lastname: Bergerheim
authors.forename: J T
authors.initials: JT
authors.lastname: Feltis
authors.forename: C
authors.initials: C
authors.lastname: Casadevall
authors.forename: A
authors.initials: A
authors.lastname: Zamarron
authors.forename: M
authors.initials: M
authors.lastname: Bernues
authors.forename: S
authors.initials: S
authors.lastname: Richard
authors.forename: C J
authors.initials: CJ
authors.lastname: Lips
authors.forename: M M
authors.initials: MM
authors.lastname: Walther
authors.forename: L C
authors.initials: LC
authors.lastname: Tsui
authors.forename: L
authors.initials: L
authors.lastname: Geil
authors.forename: M L
authors.initials: ML
authors.lastname: Orcutt
authors.forename: T
authors.initials: T
authors.lastname: Stackhouse
authors.forename: J
authors.initials: J
authors.lastname: Lipan
authors.forename: L
authors.initials: L
authors.lastname: Slife
authors.forename: H
authors.initials: H
authors.lastname: Brauch
authors.forename: J
authors.initials: J
authors.lastname: Decker
authors.forename: G
authors.initials: G
authors.lastname: Niehans
authors.forename: M D
authors.initials: MD
authors.lastname: Hughson
authors.forename: H
authors.initials: H
authors.lastname: Moch
authors.forename: S
authors.initials: S
authors.lastname: Storkel
authors.forename: M I
authors.initials: MI
authors.lastname: Lerman
authors.forename: W M
authors.initials: WM
authors.lastname: Linehan
authors.forename: B
authors.initials: B
authors.lastname: Zbar
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001665:Binding Sites; D002291:Carcinoma, Papillary / Q000453:epidemiology / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000453:epidemiology / Q000235:genetics; D002897:Chromosomes, Human, Pair 7; D005260:Female; D008040:Genetic Linkage; D018095:Germ-Line Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases