Knudson’s two-hit hypothesis states that tumour formation is initiated by biallelic inactivation of a tumour suppressor gene, and that both inherited and sporadic cancers can arise as a result of mutations in the same gene (Knudson 1971). Inherited predisposition to tumourigenesis results from a heterozygous mutation in a tumour suppressor gene, e.g. FLCN, (the ‘first hit’), but that this alone is not sufficient for tumour development; inactivation of the wild-type allele by a somatic mutation (the ‘second hit’) is required.
Somatic mutations in the remaining wild-type copy of FLCN and a loss of heterozygosity at chromosome 17p11.2 have been identified in BHD-associated renal tumours, supporting Knudson’s “two-hit” hypothesis and a tumour suppressor role for FLCN (Vocke et al., 2005). However, there is evidence that FLCN does not behave as a typical tumour suppressor protein. In a study of five BHD patients, van Steensel et al. (2007) found no evidence of somatic mutations and loss of heterozygosity in fibrofolliculomas, suggesting haplo-insufficiency is enough to cause benign tumour growth in the skin. This was supported by Bønsdorff et al. (2008), who, in a study of the canine equivalent of BHD syndrome, found ‘second hit’ FLCN mutations in kidney tumours, but not in skin nodules.
