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Recent studies facilitated by DNA sequencing identified the histone modifying gene SETD2 as the second most frequent mutant gene in sporadic clear cell renal cell carcinoma (ccRCC) patients. SETD2 functions as a tumor suppressor in ccRCC. However, its clinical association and biological functions are not fully delineated. The aim of this study is to evaluate the clinical significance of SETD2 in ccRCC patients. SETD2 and its canonical histone modification product H3K36me3 were analyzed by immunohistochemistry (IHC) in 155 ccRCC patients from two independent cohorts retrospectively. Both SETD2 and H3K36me3 were heterogeneously stained and down-regulated in ccRCC tissues, compared with normal controls. The SETD2 protein deficiency rate was 34.07%, which is much higher than the reported SETD2 gene inactive mutation rate. Furthermore, low SETD2 protein expression, but not H3K36me3 expression, was associated with the aggressive phenotype of ccRCC patients. In addition, cox multivariate analysis identified low SETD2 protein expression as an independent prognostic factor for overall survival of ccRCC patients. Consistently, using RNA-Seq data of ccRCC patients from The Cancer Genome Atlas, we validated our findings that low SETD2 mRNA expression is significantly associated with the aggressive phenotypes, and predicted a worse outcome for ccRCC patients. In conclusion, our study demonstrated a massive down-regulation of SETD2 protein in ccRCC, and identified SETD2 protein, but not H3K36me3, as an independent good prognostic marker, which warrants further study focusing on the non-methyltransferase role of SETD2 in kidney tumor biology.

Loss of SETD2, but not H3K36me3, correlates with aggressive clinicopathological features of clear cell renal cell carcinoma patients