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Epigenetics in renal cell cancer: mechanisms and clinical applications

Nature Reviews Urology volume 15, pages 430–451 (2018)Cite this article

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Abstract

Renal cell carcinoma (RCC) is characterized by an infrequent number of somatic mutations. By contrast, epigenetic aberrations are commonly found in RCC, indicating that epigenetic reprogramming is an important event in RCC development. Epigenetic alterations comprise several different aberrations, such as changes in histone modifications, DNA methylation, and microRNA levels, and occur in the most important signalling pathways in RCC, such as the von Hippel–Lindau disease tumour suppressor (VHL)–hypoxia-inducible factor (HIF) pathway, the WNT–β-catenin pathway, and pathways involved in epithelial–mesenchymal transition. Owing to their involvement in these pathways and frequent occurrence in RCC, epigenetic alterations are regarded as potential biomarkers for the early detection of disease and for prediction of prognosis and treatment response. In addition, most of these alterations are potentially reversible, so they also provide new targets for therapy. At the moment, epigenetic biomarkers for RCC are not being used in clinical practice, but targeted epigenetic therapies are under investigation. Understanding the extent of epigenetic changes occurring in RCC and the mechanisms by which they influence disease progression and treatment response, as well as knowledge of current research on biomarkers and treatments, is crucial to successful clinical translation of epigenetics in RCC.

Key points

  • Somatic mutations occur infrequently in renal cell carcinoma (RCC) and, for a long time, mutations in VHL were the only commonly found genetic aberrations.

  • Exome sequencing also revealed relatively frequent mutations in genes that encode histone-modifying and chromatin-modifying proteins, implicating epigenetic reprogramming as a key feature of renal carcinogenesis.

  • Epigenetic modifications are frequent in RCC, and important signalling pathways are epigenetically deregulated by aberrant promoter methylation of pathway components or by abnormal expression of microRNAs.

  • Epigenetic alterations might be promising biomarkers for RCC diagnosis, as well as for prognosis and prediction of therapy response in patients with RCC, and provide new targets for therapy.

  • Despite great interest in epigenetic alterations in RCC, no epigenetic markers are currently used in the clinic, and the quality of research and reporting has to be improved to enable clinical translation.

  • Therapeutic targeting of the epigenome might be attractive in RCC; in particular, the combination of epigenetic therapy and antiangiogenic or immune checkpoint treatments is a promising paradigm that could overcome frequent monotherapy resistance.

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Fig. 1: Overview of the epigenetic regulation of gene expression.
Fig. 2: Epigenetic deregulation of the VHL–HIF pathway in RCC.
Fig. 3: Effect of epigenetic alterations on key signalling pathways in RCC.

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Authors and Affiliations

  1. Division of Medical Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands

    Sophie C. Joosten, Kim M. Smits, Maureen J. Aarts & Vivianne C. Tjan-Heijnen

  2. Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands

    Kim M. Smits, Veerle Melotte, Alexander Koch & Manon van Engeland

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  1. Sophie C. Joosten
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Contributions

S.C.J. researched data for the article. S.C.J., K.M.S., M.J.A., V.C.T.-H., and M.v.E. made substantial contributions to discussion of the article content. S.C.J. and K.M.S. wrote the manuscript. K.M.S., M.J.A., V.M., A.K., V.C.T.-H., and M.v.E. reviewed and/or edited the manuscript before submission.

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Correspondence to Manon van Engeland.

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M.v.E. receives research funding from MDxHealth. S.C.J., K.M.S., M.J.A., V.M., A.K. and V.C.T.-H. declare no competing interests.

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Joosten, S.C., Smits, K.M., Aarts, M.J. et al. Epigenetics in renal cell cancer: mechanisms and clinical applications. Nat Rev Urol 15, 430–451 (2018). https://doi.org/10.1038/s41585-018-0023-z

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