Sporadic clear cell renal cell carcinoma (cRCC) is genetically characterized by the recurrent loss of the short arm of chromosome 3, with a hotspot for copy number loss in the 3p21 region. We applied a method called "gene identification by nonsense-mediated mRNA decay inhibition" to a panel of 10 cRCC cell lines with 3p21 copy number loss to identify biallelic inactivated genes located at 3p21. This revealed inactivation of the histone methyltransferase gene SETD2, located on 3p21.31, as a common event in cRCC cells. SETD2 is nonredundantly responsible for trimethylation of the histone mark H3K36. Consistent with this function, we observed loss or a decrease of H3K36me3 in 7 out of the 10 cRCC cell lines. Identification of missense mutations in 2 out of 10 primary cRCC tumor samples added support to the involvement of loss of SETD2 function in the development of cRCC tumors. Cancer Res; 70(11); 4287-91. ©2010 AACR.

Clear cell renal cell carcinomas are characterized by 3p loss, and by inactivation of Von Hippel Lindau (VHL), a tumorsuppressor gene located at 3p25. Recently, SETD2, located at 3p21, was identified as a new candidate ccRCC tumor-suppressor gene. The combined mutational frequency in ccRCC tumors of VHL and SETD2 suggests that there are still undiscovered tumor-suppressor genes on 3p. We screened all genes on 3p for mutations in 10 primary ccRCC tumors using exome-sequencing. We identified inactivating mutations in VHL, PBRM1, and BAP1. Sequencing of PBRM1 in ccRCC-derived cell lines confirmed its frequent inactivation in ccRCC. PBRM1 encodes for BAF180, the chromatin targeting subunit of the SWI/SNF complex. BAP1 encodes for BRCA1 associated protein-1, involved in histone deubiquitination. Taken together, the accumulating data suggest an important role for aberrant chromatin regulation in ccRCC development.

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