Familial non-VHL Clear Cell (Conventional) Renal Cell Carcinoma: clinical features, segregation analysis and mutation analysis of FCLN


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Emma R Woodward1, Christopher Ricketts1, Pip Killick1, Sophie Gad2, Mark Morris1, Fred Kavalier3, Shirley V Hodgson4, Sophie Giraud5, Brigitte Bressac2, Cyril Chapman6, Bernard Escudier2, Farida Latif1, Stéphane Richard2, Eamonn R Maher1

1Cancer Research UK Renal Molecular Oncology Group and Department of Medical and Molecular Genetics, University of Birmingham, Birmingham, UK, 2Institut de Cancérologie Gustave Roussy, Villejuif, France, 3Department of Clinical Genetics, Guy's Hospital, London, UK, 4Department of Medical Genetics, St George’s University of London, London, UK, 5Laboratoire de Génétique, Hôpital Edouard Herriot, Lyon, France, 6West Midlands Regional Genetics Service, Birmingham Women’s Hospital, Birmingham, UK

Abstract

Background

Familial renal cell carcinoma (RCC) is genetically heterogeneous. The most common histopathological 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 unrecognised BHD syndrome might be present in patients with apparent non-syndromic RCC susceptibility.

Method

We analysed 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 RCC susceptibility. We also undertook FLCN analysis to evaluate whether unrecognised BHD syndrome might be present in 69 patients with apparent non-syndromic RCC susceptibility.

Results

FcRCC was characterised by an earlier age at onset than sporadic cases and more frequent occurrence of bilateral or multicentric tumours. Segregation analysis demonstrated autosomal dominant inheritance with sex and age-dependent penetrance. A germline FLCN mutation was detected in 3/69 (4.3%) patients with apparent non-syndromic RCC susceptibility.

Conclusion

We describe the clinical and genetic features of the largest series of FcRCC susceptibility and recommend these patients be offered FLCN analysis, in addition to constitutional cytogenetic and VHL analysis.

Background

Familial renal cell carcinoma (RCC) is genetically heterogeneous. The most common histopathological 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 unrecognised BHD syndrome might be present in patients with apparent non-syndromic RCC susceptibility.

Method

We analysed 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 RCC susceptibility. We also undertook FLCN analysis to evaluate whether unrecognised BHD syndrome might be present in 69 patients with apparent non-syndromic RCC susceptibility.

Results

FcRCC was characterised by an earlier age at onset than sporadic cases and more frequent occurrence of bilateral or multicentric tumours. Segregation analysis demonstrated autosomal dominant inheritance with sex and age-dependent penetrance. A germline FLCN mutation was detected in 3/69 (4.3%) patients with apparent non-syndromic RCC susceptibility.

Conclusion

We describe the clinical and genetic features of the largest series of FcRCC susceptibility and recommend these patients be offered FLCN analysis, in addition to constitutional cytogenetic and VHL analysis.