Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes

Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterised by the presence of inactivating mutations in the VHL gene in the majority of cases1,2 and by infrequent somatic mutations in known cancer genes. To elucidate further the genetics of ccRCC, we have sequenced 101 cases through 3544 protein coding genes. Here we report the identification of inactivating mutations in two genes encoding enzymes involved in histone modification, SETD2, a histone H3 lysine 36 methyltransferase and JARID1C (KDM5C), a histone H3 lysine 4 demethylase in addition to mutations in the histone H3 lysine 27 demethylase, UTX (KMD6A), we recently reported3. The results highlight the role of mutations in components of the chromatin modification machinery in human cancer. Additionally, NF2 mutations were found in non-VHL mutated ccRCC and several other likely cancer genes were identified. These results indicate that substantial genetic heterogeneity exists in a cancer type dominated by mutations in a single gene and that systematic screens will be key to fully elucidating the somatic genetic architecture of cancer.