cis‐Regulatory Driver Mutations in Cancer Genomes


The increasing availability of large‐scale whole cancer genome sequencing data sets has enabled research efforts to focus on cancer driver mutations within the noncoding genome. cis‐Regulatory elements are sites responsible for the control of gene expression. Mutations at such loci may modify transcription factor binding sites, disrupt enhancer–promoter interactions or affect epigenetic marks. cis‐Regulatory driver mutations have been found in some cancer types to‐date, with initial discoveries of point mutations in the TERT promoter, small insertions creating an enhancer regulating TAL1 and genomic rearrangements leading to simultaneous enhancer dysregulation of EVI1 and GATA2. However, recent discoveries have also revealed mechanisms responsible for the accumulation of recurrent, and even functional, somatic single‐nucleotide mutations in regulatory regions, wholly apart from selective pressure. Close scrutiny of candidate cis‐regulatory mutations is necessary in order to effectively identify mutations that have undergone positive selection and to accurately distinguish driver from passenger mutations.

Key Concepts

  • Improvements in DNA sequencing technology, and the commencement of large‐scale cancer genome sequencing projects, have made discoveries in the noncoding genome possible.
  • cis‐Regulatory elements, such as promoters and enhancers, are responsible for the control of gene expression.
  • Transcription factors bind to cis‐regulatory elements, influencing the rate of transcription of DNA to mRNA.
  • Mutations in cis‐regulatory elements can drive cancer development by altering transcription factor binding sites, enhancer–promoter interactions or the epigenetic landscape of the cell.
  • Alterations to cis‐regulatory elements can lead to gene dysregulation, potentially impacting the expression of oncogenes or tumour suppressor genes.
  • Recurrent somatic driver mutations affecting cis‐regulatory elements have already been identified in cancer genomes, including point mutations, insertions and deletions (indels) and structural rearrangements.
  • cis‐Regulatory elements may appear recurrently mutated in cancer due to selective pressures or due to other mechanisms driving the formation of mutation hot spots.
  • Transcription factor binding can inhibit access to nucleotide excision repair (NER) enzymes, leading to increased mutation rates at transcription factor binding sites in some cancers.
  • DNA modifications and nucleotide composition can both influence the propensity for certain sites to become mutated.
  • Close scrutiny of candidate cis‐regulatory mutations is necessary in order to effectively identify sites under selective pressure and to accurately distinguish driver from passenger mutations.

Keywords: cis‐regulation; promoter; enhancer; somatic mutation; cancer; driver; transcription factor; gene expression; DNA repair

Figure 1. Enhancer–promoter interactions occurring between cis‐regulatory elements within chromatin domains.(a) Enhancer–promoter interaction via looping of genomic DNA. Promoter and enhancer elements physically interact over large regions of genomic DNA (deoxyribonucleic acid), recruiting transcription factors and the transcription initiation complex, to regulate gene transcription and the production of messenger ribonucleic acid (mRNA). (b) Chromatin domains defined by the binding of CTCF.CCCTC‐binding factor (CTCF) binds to regions of DNA and, together with the cohesin protein, creates chromatin compartments called topologically associating domains (TADs). TADs contain a higher than average density of interactions between internal cis‐regulatory elements. P denotes a promoter and E denotes an enhancer.
Figure 2. Types of somatic mutations that can cause alterations to cis‐regulatory elements.(a) Single‐nucleotide point mutation creating a novel transcription factor binding site. Similar to the TERT promoter mutations (Horn et al., ; Huang et al., ), this schematic depicts a single‐nucleotide point mutation in a promoter element which creates a binding site for a certain transcription factor, leading to increased promoter activity and gene expression. (b) Insertion mutation creating a novel enhancer element. Similar to the novel TAL1 enhancer (Mansour et al., ), this schematic depicts the creation of an enhancer element due to a small DNA insertion which aberrantly recruits transcription factors. The novel enhancer physically interacts with a promoter element some distance away and dysregulates downstream gene expression. (c) Structural rearrangement resulting in dysregulation of enhancer–promoter interactions. Similar to the EVI1/GATA2 enhancer rearrangement (Groschel et al., ), this schematic depicts a structural rearrangement within a chromosome that rewires enhancer–promoter interactions and leads to gene dysregulation.
Figure 3. Inhibition of nucleotide excision repair resulting from transcription factor binding. The binding of transcription factors can block access to nucleotide excision repair machinery, leaving DNA lesions unrepaired and leading to localised increases in mutation rates at transcription factor binding sites in some cancers (Perera et al., ; Sabarinathan et al., ). Regions of open chromatin are otherwise accessible to repair enzymes and, consequently, tend to have reduced mutation loads (Polak et al., ).
Figure 4. DNase I hypersensitivity sequencing (DNase‐seq) methodology. Regions which are nucleosome free are hypersensitive to the endonuclease enzyme DNase I. This means that they are preferentially cleaved by this enzyme, with sites of reduced nucleosome occupancy able to be identified by sequencing the DNA fragments produced by enzyme cleavage (Boyle et al., ).
Figure 5. Chromatin immunoprecipitation sequencing (ChIP‐seq) methodology. DNA–protein complexes can be captured using a protein‐specific antibody, with regions bound by the target protein identified by sequencing the resultant DNA fragments (Johnson et al., ).


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Further Reading

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Poulos RC, Sloane MA, Hesson LB and Wong JW (2015) The search for cis‐regulatory driver mutations in cancer genomes. Oncotarget 6 (32): 32509–32525.

Poulos RC and Wong JW (2016) Mutation hotspots in cis‐regulatory regions in cancer. Oncoscience 3 (11–12): 318–319.

Tubbs A and Nussenzweig A (2017) Endogenous DNA damage as a source of genomic instability in cancer. Cell 168 (4): 644–656.

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Poulos, Rebecca C, and Wong, Jason WH(Jun 2017) cis‐Regulatory Driver Mutations in Cancer Genomes. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027236]