A novel map of human p53 response elements uncovers evidence of selection pressures and variants similar to Li-Fraumeni Syndrome mutations

BackgroundThe 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. MethodsIn 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. ResultsWe 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. ConclusionsTogether, 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.