title: Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene.
abstract: OBJECTIVE
  Hereditary papillary renal carcinoma (HPRC) is characterized by a predisposition to multiple, bilateral papillary type 1 renal tumors caused by inherited activating missense mutations in the tyrosine kinase domain of the MET proto-oncogene. In the current study we evaluated the clinical phenotype and germline MET mutation of 3 new HPRC families. We describe the early onset clinical features of HPRC.
  
  
  METHODS
  We identified new HPRC families of Italian (family 177), Spanish (family 223) and Cuban (family 268) descent. We evaluated their clinical features, performed MET mutation analysis by denaturing high performance liquid chromatography and DNA sequencing, and estimated age dependent penetrance and survival using Kaplan-Meier analysis. We characterized renal tumors by histology and fluorescence in situ hybridization.
  
  
  RESULTS
  Identical germline MET c.3522G --> A mutations (V1110I) were identified in families 177 and 268 but no evidence of a founder effect was found. Affected members of family 223 carried a germline c.3906G --> C.3522G --> A MET mutation (V1238I). Age dependent penetrance but not survival was significantly earlier for the c.3522G -->A mutation than for the c.3906G --> A mutation in these HPRC families. Trisomy of chromosome 7 and papillary renal carcinoma type 1 histology were detected in papillary renal tumors.
  
  
  CONCLUSIONS
  HPRC can occur in an early onset form. The median age for renal tumor development in these 3 HPRC families was 46 to 63 years. HPRC associated papillary renal tumors may be aggressive and metastasize, leading to mortality. Median survival age was 60 to 70 years. Families with identical germline mutations in MET do not always share a common ancestor. HPRC is characterized by germline mutations in MET and papillary type 1 renal tumor histology.
authors.affiliation: Basic Research Program, SAIC-Frederick, Inc., Frederick, Maryland, USA. schmidtl@mail.ncifcrf.gov
authors.forename: Laura S
authors.initials: LS
authors.lastname: Schmidt
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nickerson
authors.forename: Debora
authors.initials: D
authors.lastname: Angeloni
authors.forename: Gladys M
authors.initials: GM
authors.lastname: Glenn
authors.forename: McClellan M
authors.initials: MM
authors.lastname: Walther
authors.forename: Paul S
authors.initials: PS
authors.lastname: Albert
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Warren
authors.forename: Peter L
authors.initials: PL
authors.lastname: Choyke
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Torres-Cabala
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Merino
authors.forename: Joan
authors.initials: J
authors.lastname: Brunet
authors.forename: Victòria
authors.initials: V
authors.lastname: Bérez
authors.forename: Joan
authors.initials: J
authors.lastname: Borràs
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sesia
authors.forename: Lindsay
authors.initials: L
authors.lastname: Middelton
authors.forename: John L
authors.initials: JL
authors.lastname: Phillips
authors.forename: Catherine
authors.initials: C
authors.lastname: Stolle
authors.forename: Berton
authors.initials: B
authors.lastname: Zbar
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Pautler
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
mesh_terms: D000231:Adenocarcinoma, Papillary / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000367:Age Factors; D000368:Aged; D002897:Chromosomes, Human, Pair 7; D005091:Exons; D005260:Female; D006580:Genetic Carrier Screening; D018095:Germ-Line Mutation; D006801:Humans; D007668:Kidney / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009378:Neoplasms, Multiple Primary / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010375:Pedigree; D019683:Penetrance; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor; D016019:Survival Analysis; D014314:Trisomy; D018909:src Homology Domains / Q000235:genetics
chemical_list: C000715470:MAS1 protein, human; D011506:Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; C491743:MET protein, human; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met