Understanding the impact of loss or depletion of SETD2 and H3K36me3 on DNA methylation is of particular clinical relevance as SETD2 is frequently mutated in multiple cancer types, for example, in up to 16% of clear cell renal cell carcinomas (ccRCC) and can be as high as 30% in metastatic ccRCC [22, 23]. This evidence concerns the gene SETD2 and nonpapillary renal cell carcinoma.