Renal cell carcinoma (RCC) is not a single entity, but comprises a group of
tumors including clear cell RCC, papillary RCC and chromophobe RCC, which arise from the epithelium of renal tubules. The majority of clear cell RCCs, the major histological subtype, have genetic or epigenetic inactivation of the von Hippel-Lindau (VHL) gene. Germline mutations in the MET and
fumarate hydratase (FH) genes lead to the development of type 1 and type 2 papillary RCCs, respectively, and such mutations of either the TSC1 or TSC2 gene increase the risk of RCC. Genome-wide copy number alteration analysis has suggested that loss of chromosome 3p and gain of chromosomes 5q and 7 may be copy number aberrations indispensable for the development of clear cell RCC. When chromosome 1p, 4, 9, 13q or 14q is also lost, more clinicopathologically aggressive clear cell RCC may develop. Since renal
carcinogenesis is associated with neither chronic
inflammation nor persistent
viral infection, and hardly any histological change is evident in corresponding non-tumorous renal tissue from patients with renal
tumors,
precancerous conditions in the kidney have been rarely described. However, regional
DNA hypermethylation on C-type CpG islands has already accumulated in such non-cancerous renal tissues, suggesting that, from the viewpoint of altered DNA methylation, the presence of
precancerous conditions can be recognized even in the kidney. Genome-wide DNA methylation profiles in
precancerous conditions are basically inherited by the corresponding clear cell RCCs developing in individual patients: DNA methylation alterations at the precancerous stage may further predispose renal tissue to epigenetic and genetic alterations, generate more malignant
cancers, and even determine patient outcome. The list of
tumor-related genes silenced by
DNA hypermethylation has recently been increasing. Genetic and epigenetic profiling provides an optimal means of prognostication for patients with RCCs. Recently developed high-throughput technologies for genetic and epigenetic analyses will further accelerate the identification of key molecules for use in the prevention, diagnosis and
therapy of RCCs.