Familial non-VHL clear cell (conventional) renal cell carcinoma: clinical features, segregation analysis, and mutation analysis of FLCN.
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.
Woodward
Emma R
ER
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
Ricketts
Christopher
C
Killick
Pip
P
Gad
Sophie
S
Morris
M R
MR
Kavalier
Fred
F
Hodgson
Shirley V
SV
Giraud
Sophie
S
Bressac-de Paillerets
Brigitte
B
Chapman
Cyril
C
Escudier
Bernard
B
Latif
Farida
F
Richard
Stéphane
S
Maher
Eamonn R
ER
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
C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins