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

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 withoutVHL 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.

A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene

“…The database lists previously published point mutations, deletions, duplications and splice site mutations in the FLCN gene (Bessis et al, 2006;Cho et al, 2008;Frohlich et al, 2008;Gad et al, 2007,Graham et al, 2005Gunji et al, 2007;Imada et al, 2009;Kawasaki et al, 2005;Khoo et al, 2002;Kim et al, 2008;Lamberti et al, 2005;Leter et al, 2008;Murakami et al, 2007;Nickerson et al, 2002;Painter et al, 2005;Palmirotta et al, 2008;Ren et al, 2008;Schmidt et al, 2005;Toro et al, 2008;van Steensel et al, 2007;Woodward et al, 2008). In addition 10 previously unpublished novel mutations/variants are included.…”

“…Germline mutations in the folliculin gene (FLCN) were first identified in BHD patients in 2002 (Nickerson et al, 2002). In addition, FLCN mutations have also been discovered in patients with familial Primary Spontaneous Pneumothorax (PSP; MIM# 173600) and cases presenting with familial clear cell renal carcinoma (FcRCC) in whom other features of BHD have not been noted (Frohlich et al, 2008;Graham et al, 2005;Gunji et al, 2007;Painter et al, 2005;Ren et al, 2008;Woodward et al, 2008) …”

Differential Diagnosis of Renal Tumors With Clear Cytoplasm: Clinical Relevance of Renal Tumor Subclassification in the Era of Targeted Therapies and Personalized Medicine

“…87 To date, however, studies in which FLCN mutational analysis was performed on renal tumors believed to be sporadic have failed to demonstrate any such alterations or, when mutations have been identified, they have ultimately been shown to be germline mutations. [88][89][90][91] Studies evaluating ChRCC for VHL inactivation and 3p losses have shown that these tumors lack these changes and the subsequent activation of the HIF pathway as seen in CCRCC. 58 Thus, the molecular rationale for treating these tumors with currently available targeted therapies is lacking, possibly explaining the decreased response rates seen in ChRCC relative to CCRCC when such therapies are used.…”

Genetic Syndromes Associated With Renal Cell Carcinoma - A Review

“…Familial ccRCC is defined as the development of ccRCC in two or more members of the same family, in whom VHL disease and constitutional chromosome 3 translocation have been ruled out 38,39,7,14 . This type of tumour is associated with a very low frequency (over 70 families have been reported).…”