The advent of functional genomic techniques and next generation sequencing has improved the characterization of the non-protein coding regions of the genome. However, the integration of these data into clinical practice is still in its infancy. Fifty percent of cancers mutate TP53, which promotes tumorigenesis, in part, by inhibiting its ability to bind to non-coding regions of the genome and function as a sequence-specific transcription factor. P53 is a tumour suppressor that inhibits cell survival through regulating transcription of anti-survival genes. However, p53 also regulates transcription of pro-survival genes and the target gene(s) responsible for p53 tumour suppression remains an open topic of research. In this study, we integrate detailed genome-wide maps of p53 responsive elements (p53-RE), p53 occupancy, recently defined candidate cis-Regulatory Elements (cCREs) and whole genome sequencing for cancers to better define the regions of the genome that harbour functional p53 enhancers. We determine that p53-REs are more likely to be closer to the consensus binding site, to be evolutionarily conserved and to be occupied by p53 in cellulo, when they reside in regions of the genome that have been noted to have accessible DNA and a regulatory epigenomic mark in at least one human cell even without obvious p53 activation signals (cCRE p53-REs). We offer evidence that it is only in cCRE p53-REs, where multiple signs of differential natural selection between pro-survival and anti-survival target genes can be noted. Using whole genome sequences of 38,377 individuals, we go on to demonstrate that carriers of rare germline mutations in cCRE p53-REs can have similar traits to carriers of rare p53 coding mutations that cause the Li-Fraumeni cancer predisposition syndrome. Together, these observations suggest that functional p53 enhancers are enriched in cCREs and that germline mutations in them have the potential to improve current cancer risk management and screening strategies.

The authors have declared no competing interest.

Funding for GLB for this work was provided by the Ludwig Institute for Cancer Research and University of Birmingham. PZ was funded in part by the Ludwig Institue for Cancer Research. DB was funded by the University of Birmingham. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. AMF and NP are supported by the National Institute for Health Research, UCLH Biomedical Research Centre and the UCL Experimental Cancer Centre. SDN holds a Jean Shanks Foundation - Pathological Society Clinical PhD Fellowship. PVL was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202), and the Wellcome Trust (FC001202).

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Genomics England 100K genomes project

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