Importantly, we find that in renal cancer, these DNA methylation changes are significantly correlated with gene expression changes in oncogenes and tumour suppressors, including TP53, FOXO1, and CDK4. Genes with dysregulated expression that correlated with SETD2-dependent DNA methylation changes are enriched for tumorigenic processes such as neoplasm invasiveness, suggesting a new role for SETD2 in tumorigenesis and cancer aggressiveness through DNA methylation dysregulation. Here, CDK4 is linked to cancer.