FaCD Online Syndrome Fact Sheet

Last updated: 27 Jun 2012

Name: Familial Non-VHL Clear Cell Renal Cancer

Synonym: Familial Clear Cell Renal Cell Cancer, FcRCC, Familial Non-VHL Non-Papillary Clear Cell Renal Cancer

Mode of Inheritance: AD

Genes

FLCN, mapped to 17p11.2
KILLIN, mapped to 10q23
MITF, mapped to 3p14-p13

Tumor features

renal cell cancer, clear-cell (Grawitz tumor)

Comment

Familial clustering suggestive of hereditary clear cell renal cancer (CCRC) in the absence of signs of von Hippel-Lindau disease has been reported. In contrast to two non-VHL CCRC families reported earlier, Woodward et al.[1] observed early onset of disease (52% <50 yrs) in 9 families with 2 or more first-degree relatives with CCRC.

The disorder does not map to the VHL locus[2] or the MET locus (associated with hereditary papillary renal cell cancer)[3] and no germline mutations have been detected in VHL and MET genes[1;4]. Large familial non-syndromic clear cell RCC kindreds are uncommon and for a long time efforts to identify the predisposing gene defect in these families were unsuccesful[5]. Recently, however, Woodward et al identified germline FLCN mutations in 4% of families with familial clustering of non-VHL clear cell renal cell cancer[6]. FLCN is the gene commonly associated with Birt-Hogg-Dubé syndrome. Bennett et al [7] have identified germline KILLIN promoter hypermethylation in 56% of 43 individuals diagnosed with CCRCC compared to no germline methylation in population controls. KILLIN inactivation has also been associated with Cowden syndrome and Cowden-like phenotypes.

Berlotto et al[8] investigated patients with melanoma and/or renal cancer. They identified the E318K MITF variant as a gain-of-function mutation in this group and showed that carriers had a higher than fivefold increased risk of developing melanoma, RCC (clear cell or papillary type 1) or both cancers.

References

[1] Woodward ER, Clifford SC, Astuti D, Affara NA, Maher ER. Familial clear cell renal cell carcinoma (FCRC): clinical features and mutation analysis of the VHL, MET, and CUL2 candidate genes. Journal of medical genetics 2000; 37(5):348-53.
[2] Teh BT, Giraud S, Sari NF, Hii SI, Bergerat JP, Larsson C, Limacher JM, Nicol D. Familial non-VHL non-papillary clear-cell renal cancer. Lancet 349[9055], 848-849. 1997.
[3] Teh BT, Nord B, Kytola S, Giraud S, Arver B, Limacher JM, Gross D, Nicol D. Familial non-VHL, non papillary renal cell carcinoma. Am J Hum Genet 63[4 suppl], A88. 1998. Ref Type: Abstract
[4] Woodward E, Rose S, Schmidt L, Affara NA, Maher ER. Mutations analysis of the MET proto-oncogene and the von Hippel-Lindau (VHL) tumour suppressor gene in familial renal cell carcinoma. J Med Genet 1997; 34(suppl.1):S39.
[5] Woodward ER. Familial non-syndromic clear cell renal cell carcinoma. Current molecular medicine 2004; 4(8):843-8.
[6] Woodward ER, Ricketts C, Killick P, Gad S, Morris MR, Kavalier F, Hodgson SV, Giraud S, Bressac-de Paillerets B, Chapman C, Escudier B, Latif F, Richard S, Maher ER. Familial Non-VHL Clear Cell (Conventional) Renal Cell Carcinoma: Clinical Features, Segregation Analysis, and Mutation Analysis of FLCN. Clinical cancer research 2008; 14(18):5925-30.
[7] Bennett KL, Campbell R, Ganapathi S, Zhou M, Rini B, Ganapathi R, Neumann HP, Eng C. Germline and somatic DNA methylation and epigenetic regulation of KILLIN in renal cell carcinoma. Genes Chromosomes Cancer. 2011 Aug;50(8):654-61.
[8] Bertolotto C et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 2011; 480:94-8.