Genetic heterogeneity and chromatin modifiers in renal clear cell carcinoma

Evaluation of: Dalgliesh GL, Furge K, Greenman C et al.: Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360-363 (2010). Clear cell renal cell carcinoma (ccRCC) accounts for more than 75% of all adult kidney cancer. Hereditary ccRCC in von Hippel-Lindau disease is caused by germline mutations of the VHL tumor suppressor gene. Moreover, 50% of sporadic ccRCCs harbor biallelic mutations of VHL. However, loss of VHL alone is insufficient for tumor initiation, and a minority of ccRCCs retain wild-type VHL alleles, indicating a requirement for additional or alternative genetic alterations in tumor development. This systematic study demonstrated that a fraction of ccRCCs harbored inactivating mutations in four genes encoding histone-modifying enzymes. One of these, UTX, has recently been implicated in the control of cell proliferation. Moreover, several other mutations were identified, among them NF2 truncations in a subset of VHL-positive ccRCC. The study illustrates both a vast genetic heterogeneity in ccRCC and a requirement for further systematic investigations to design a targeted treatment for different ccRCC subtypes.