title: Familial non-VHL clear cell (conventional) renal cell carcinoma: clinical features, segregation analysis, and mutation analysis of FLCN.
abstract: OBJECTIVE
  Familial renal cell carcinoma (RCC) is genetically heterogeneous. The most common histopathologic subtype of sporadic and familial RCC is clear cell (cRCC) and von Hippel-Lindau (VHL) disease is the most common cause of inherited cRCC. Familial cRCC may also be associated with chromosome 3 translocations and has recently been described in patients with Birt-Hogg-Dube (BHD) syndrome, caused by germline FLCN mutation. Fewer than 20 kindreds with familial cRCC without VHL disease or a constitutional translocation have been described. The purpose of this investigation was to define the clinical and genetic features of familial non-VHL cRCC (FcRCC) and to evaluate whether unrecognized BHD syndrome might be present in patients with apparent nonsyndromic RCC susceptibility.
  
  
  METHODS
  We analyzed the clinical features of, and undertook segregation analysis in, 60 kindreds containing two or more cases of RCC (at least one confirmed case of cRCC) and no evidence of an RCC susceptibility syndrome. We also undertook FLCN analysis to evaluate whether unrecognized BHD syndrome might be present in 69 patients with apparent nonsyndromic RCC susceptibility.
  
  
  RESULTS
  FcRCC was characterized by an earlier age at onset than sporadic cases and more frequent occurrence of bilateral or multicentric tumors. Segregation analysis showed autosomal dominant inheritance with sex- and age-dependent penetrance. A germline FLCN mutation was detected in 3 of 69 (4.3%) patients with apparent nonsyndromic RCC susceptibility.
  
  
  CONCLUSIONS
  We describe the clinical and genetic features of the largest series of FcRCC and recommend these patients be offered FLCN analysis, in addition to constitutional cytogenetic and VHL analysis.
authors.affiliation: Cancer Research UK Renal Molecular Oncology Group and Department of Medical and Molecular Genetics, University of Birmingham and West Midlands Regional Genetics Service, Birmingham Women's Hospital, United Kingdom. E.R.Woodward@bham.ac.uk
authors.forename: Emma R
authors.initials: ER
authors.lastname: Woodward
authors.forename: Christopher
authors.initials: C
authors.lastname: Ricketts
authors.forename: Pip
authors.initials: P
authors.lastname: Killick
authors.forename: Sophie
authors.initials: S
authors.lastname: Gad
authors.forename: M R
authors.initials: MR
authors.lastname: Morris
authors.forename: Fred
authors.initials: F
authors.lastname: Kavalier
authors.forename: Shirley V
authors.initials: SV
authors.lastname: Hodgson
authors.forename: Sophie
authors.initials: S
authors.lastname: Giraud
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bressac-de Paillerets
authors.forename: Cyril
authors.initials: C
authors.lastname: Chapman
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Farida
authors.initials: F
authors.lastname: Latif
authors.forename: Stéphane
authors.initials: S
authors.lastname: Richard
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D020090:Chromosome Segregation; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000235:genetics
chemical_list: C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins