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Epigenetic modifiers: activities in renal cell carcinoma

Abstract

Renal cell carcinomas (RCCs) are a diverse set of malignancies that have recently been shown to harbour mutations in a number of chromatin modifier genes — including PBRM1, SETD2, BAP1, KDM5C, KDM6A, and MLL2 — through high-throughput sequencing efforts. Current research focuses on understanding the biological activities that chromatin modifiers employ to suppress tumorigenesis and on developing clinical approaches that take advantage of this knowledge. Unsurprisingly, several common themes unify the functions of these epigenetic modifiers, particularly regulation of histone post-translational modifications and nucleosome organization. Furthermore, chromatin modifiers also govern processes crucial for DNA repair and maintenance of genomic integrity as well as the regulation of splicing and other key processes. Many chromatin modifiers have additional non-canonical roles in cytoskeletal regulation, which further contribute to genomic stability, expanding the repertoire of functions that might be essential in tumorigenesis. Our understanding of how mutations in chromatin modifiers contribute to tumorigenesis in RCC is improving but remains an area of intense investigation. Importantly, elucidating the activities of chromatin modifiers offers intriguing opportunities for the development of new therapeutic interventions in RCC.

Key points

  • Loss-of-function mutations in chromatin modifiers, which are common in renal cell carcinoma (RCC), can modify tumour biology and influence therapeutic responses; thus, understanding how these events contribute to RCC is paramount.

  • Chromatin modifiers classically regulate genomic architecture and, therefore, control DNA accessibility; these canonical functions are fundamental for essential cellular processes, such as gene expression programmes and DNA damage repair.

  • Chromatin modifiers have non-histone substrates and participate in extranuclear processes; these non-canonical functions regulate important cellular processes, such as cytoskeletal dynamics and immune responses.

  • Loss-of-function mutations in chromatin modifiers can be approached therapeutically by exploiting synthetically lethal dependencies between two genes; loss of both genes induces cell death, but loss of either is nonfatal.

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Fig. 1: Chromatin modification by PBRM1, BAP1, and SETD2.
Fig. 2: Structure and distribution of PBRM1, BAP1, and SETD2 mutations in RCC.
Fig. 3: H3K36me3 facilitates DNA damage repair.
Fig. 4: Maintenance of transcriptional fidelity.

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Acknowledgements

The authors acknowledge the support of the NIH: grants R01CA198482 (W.K.R.), K24CA172355 (W.K.R.), and T32CA009582 (A.A.d.C.). This work was performed in part at the Aspen Center for Physics, which is supported by National Science Foundation grant PHY-1607611.

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Glossary

Clear cell renal cell carcinoma

(ccRCC). The most common histological subtype of RCC, originating from cells of the proximal convoluted tubule.

Chromophobe renal cell carcinoma

(chRCC). A rare variant of RCC that is frequently characterized by mutations in PTEN and TP53 as well as the loss of chromosomes 1, 2, 6, 10, 13, 17, and 21.

Renal medullary carcinoma

A very rare renal cell carcinoma histology that occurs almost exclusively in young people of African-American descent.

Post-translational modifications

(PTMs). The covalent, and generally enzymatic, modification of proteins following protein biosynthesis.

Ubiquitylation

The process by which ubiquitin is covalently attached to substrate proteins.

Multi-region genomic profiling

Refers to a genomic analysis involving multiple samples derived from a single tumour specimen.

Type 1 pRCC

A histological subtype of papillary renal cell carcinoma (pRCC) that generally comprises indolent tumours and is characterized by activating mutations in the MET oncogene and gains in chromosome 3, 7, and 17.

Type 2 pRCC

A histological subtype of papillary renal cell carcinoma (pRCC) that generally comprises aggressive tumours and can harbour mutations in the FH gene.

Renal oncocytomas

Benign renal tumours.

Sarcomatoid RCCs

Refers to renal cell carcinoma (RCC) tumours that display sarcomatoid (or spindle-shaped cell) morphology. These variants of the conventional histological subtypes clear cell RCC (ccRCC), papillary RCC (pRCC) and chromophobe RCC (chRCC) are typically more aggressive and rapidly lethal than non-sarcomatoid variants.

DNA mismatch repair

(DNA MMR). A genomic maintenance system by which misincorporated nucleotides and insertion–deletion mispairings are removed and corrected in newly synthesized DNA.

Double-strand break repair

(DSB repair). DSBs can result from genotoxic insults, where both strands of DNA are broken as a result; if not properly repaired, DNA DSBs can result in genomic rearrangements or cell death. DSBs can be resolved either by homologous recombination or non-homologous end joining.

Homologous recombination

(HR). Refers to the DNA repair pathway that is most widely used by cells to accurately repair DNA double-strand breaks, whereby nucleotide sequences are exchanged between two similar or identical DNA molecules.

Non-homologous end joining

(NHEJ). A DNA repair pathway whereby the ends of the DNA break are directly ligated without the need for a homologous template.

Euchromatin

Refers to chromatin that is in a relaxed state and is associated with active transcription.

Cryptic transcription

An aberrant process by which polymerase initiates transcription at a location other than canonical promoters, such as in the gene body.

Nonsense-mediated decay pathway

(NMD pathway). A surveillance pathway that exists in all eukaryotes and primarily functions to reduce erroneous gene expression by eliminating mRNA transcripts that contain premature stop codons.

CpG island methylator phenotype

(CIMP). Refers to global genome hypermethylation that is thought to promote tumorigenesis by switching off tumour suppressor genes.

Differentially methylated regions

(DMRs). Genomic regions with a different DNA methylation status among a group of samples (for example, among tissues or individuals) that are regarded as possible functional regions involved in transcriptional regulation.

Micronuclei

Extranuclear bodies that contain fragments of chromosomes, resulting from erroneous cell division.

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de Cubas, A.A., Rathmell, W.K. Epigenetic modifiers: activities in renal cell carcinoma. Nat Rev Urol 15, 599–614 (2018). https://doi.org/10.1038/s41585-018-0052-7

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