Key Points
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The most common mutations in renal cancers occur in the VHL gene; they disrupt many cellular pathways, notably those involved in the hypoxic response
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Other common mutations affect genes encoding proteins involved in histone modification and chromatin remodelling; mutations of these epigenetic modifier genes influence genome-wide gene expression
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Many key pathways involved in physiological renal cell function are disrupted by inappropriate silencing of component genes through methylation of CpG regions in promoters; these disruptions contribute to renal cancer development
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Alteration of the expression of microRNAs (miRNAs) in renal cancers contributes to the disruption of important cellular networks
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In Wilms tumour, a common childhood renal cancer, miRNA maturation and degradation are often disrupted via mutations of key components of the miRNA biogenesis pathway
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Epigenetically disrupted genes in renal cancers are good candidate targets for the development of robust prognostic and diagnostic tools and novel therapeutics
Abstract
The majority of kidney cancers are associated with mutations in the von Hippel-Lindau gene and a small proportion are associated with infrequent mutations in other well characterized tumour-suppressor genes. In the past 15 years, efforts to uncover other key genes involved in renal cancer have identified many genes that are dysregulated or silenced via epigenetic mechanisms, mainly through methylation of promoter CpG islands or dysregulation of specific microRNAs. In addition, the advent of next-generation sequencing has led to the identification of several novel genes that are mutated in renal cancer, such as PBRM1, BAP1 and SETD2, which are all involved in histone modification and nucleosome and chromatin remodelling. In this Review, we discuss how altered DNA methylation, microRNA dysregulation and mutations in histone-modifying enzymes disrupt cellular pathways in renal cancers.
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Glossary
- microRNAs
-
Small, noncoding RNAs that regulate gene expression post-transcriptionally by targeting specific mRNAs for inhibition or degradation through complimentary base pairing.
- Condensed chromatin
-
Regions of chromatin where nucleosomes are closely packed together preventing transcription.
- Relaxed chromatin
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Regions of the chromatin where nucleosomes vacate promoter regions allowing access to transcription factors and the transcriptional machinery.
- CpG islands
-
Region of DNA with a high frequency of 5′–C–phosphate–G–3′ (CpG) dinucleotides. These regions are frequent around transcriptional start sites.
- CpG island methylator phenotype
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(CIMP). Tumour phenotype that is characterized by widespread and elevated levels of CpG island methylation. This phenotype represents a clinically and aetiologically distinct group
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Morris, M., Latif, F. The epigenetic landscape of renal cancer. Nat Rev Nephrol 13, 47–60 (2017). https://doi.org/10.1038/nrneph.2016.168
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DOI: https://doi.org/10.1038/nrneph.2016.168
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