Molecular characterization of SETD2, a histone methyltransferase, in clear cell renal cell carcinoma (ccRCC).

4624 Background: Although the von Hippel-Lindau (VHL) tumor suppressor is mutated in 60% of ccRCC, deletion of VHL in mice is insufficient for tumorigenesis. Sequencing of ccRCC tumors identified mutations in SETD2, a histone H3 lysine 36 (H3K36) trimethyltransferase. We hypothesize that loss of SETD2 methyltransferase activity decreases H3K36 trimethylation (H3K36Me3) in ccRCC, and contributes to the cancer phenotype. Methods: H3K36Me3 immunohistochemical (IHC) staining was quantitated in wild-type and mutant SETD2 nephrectomy tissue. To establish frequency of SETD2 loss of heterozygosity (LOH), genomic DNA was isolated from 51 VHL deficient ccRCC specimens and analyzed with Affymetrix single-nucleotide polymorphism (SNP) arrays. To evaluate alterations of histone modifications in advanced ccRCC, H3K36Me3 IHC was quantitated on tissue microarrays (TMAs) representing 28 paired ccRCC specimens with unaffected kidney parenchyma and 40 metastases. To identify kidney-specific H3K36Me3 binding sites, chromatin...