Understanding the complex epigenome of advanced renal cell carcinoma may lead to novel epigenomic-based pharmaceutical strategies and identify new targets for therapeutic interventions. Epigenetic changes, such as DNA methylation and histone acetylation, modulate the activity of significant oncogenic signaling pathways by regulating gene expression. Such pathways include the WNT-β-catenin pathway, the von Hippel-Lindau-hypoxia-inducible factor pathway, and epithelial-mesenchymal transition pathway. Common genetic alterations in histone modifier genes in renal cell carcinoma may not only be responsible for the pathogenesis of this disease but also represent potential biomarkers of response to immunotherapies. Rational combinations strategies with histone deacetylase inhibitors are being tested in clinic trials. Renal cell carcinoma represents an ideal setting to dissect the epigenetic-driven changes in the tumor microenvironment that modulate the response to targeted therapies.
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