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Familial Non-VHL Clear Cell (Conventional) Renal Cell Carcinoma: Clinical Features, Segregation Analysis, and Mutation Analysis of FLCN

Authors' Affiliations: ¹ Cancer Research UK Renal Molecular Oncology Group and Department of Medical and Molecular Genetics, University of Birmingham and ² West Midlands Regional Genetics Service, Birmingham Women's Hospital, United Kingdom; ³ Génétique Oncologique EPHE, Centre National de la Recherche Scientifique FRE-2939, Institut de Cancérologie Gustave Roussy, Villejuif, and Réseau National INCa "Prédispositions héréditaires au cancer rénal," AP-HP, Service d'Urologie, Hôpital du Kremlin-Bicêtre, Le Kremlin-Bicêtre, France; ⁴ Department of Clinical Genetics, Guy's Hospital and ⁵ Department of Medical Genetics, St. George's University of London, Cranmer Terrace, London, United Kingdom; ⁶ Laboratoire de Génétique, Hôpital Edouard Herriot, Lyon, France; and ⁷ Service de Génétique and Centre National de la Recherche Scientifique FRE-2939, Institut de cancérologie Gustave Roussy and ⁸ Département de Médecine, Institut de cancérologie Gustave Roussy, Villejuif, France

Requests for reprints: Emma R. Woodward, Clinical Genetics Unit, Birmingham Women's Hospital, Metchley Park Road, Edgbaston, Birmingham, West Midlands, B15 2TG, United Kingdom. Phone: 44-121-627-2630/44-121-627-2741; Fax: 44-121-627-2618; E-mail: E.R.Woodward{at}bham.ac.uk.

Abstract

Purpose: 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.

Experimental Design: 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.