The importance of p53 pathway genetics in inherited and somatic cancer genomes

Key Points In this Analysis, we explore the possibility that commonly inherited genetic variants in the p53 pathway play a significant part in susceptibility to a broad range of cancers. We use genome-wide datasets of genetic variation, cancer susceptibility loci derived from hundreds of genome-wide association studies conducted in a broad range of cancers, and expression quantitative trait loci (eQTLs) from eQTL databases from many different tissue types. Our results demonstrate that p53 pathway genes are more significantly enriched in cancer susceptibility loci compared with other signalling pathways. We did not find p53 pathway genes to be significantly enriched in susceptibility loci for any other major disease groupings. We observe strong similarities between the causal, somatic mutations and the inherited, cancer-associated single nucleotide polymorphisms of the p53 pathway, in which both classes of genetic variant are found to occur in a high proportion of p53 pathway genes in multiple cancer types, and in similar genes. Our results enable insights into p53-mediated tumour suppression in humans and into p53 pathway-based cancer surveillance and treatment strategies. Using genomic data, this Analysis demonstrates that commonly inherited single nucleotide polymorphisms (SNPs) occurring in genes of the p53 pathway affect the incidence of a broad range of cancers, more so than SNPs in other pathways. This has implications for p53-mediated tumour suppression in humans. Decades of research have shown that mutations in the p53 stress response pathway affect the incidence of diverse cancers more than mutations in other pathways. However, most evidence is limited to somatic mutations and rare inherited mutations. Using newly abundant genomic data, we demonstrate that commonly inherited genetic variants in the p53 pathway also affect the incidence of a broad range of cancers more than variants in other pathways. The cancer-associated single nucleotide polymorphisms (SNPs) of the p53 pathway have strikingly similar genetic characteristics to well-studied p53 pathway cancer-causing somatic mutations. Our results enable insights into p53-mediated tumour suppression in humans and into p53 pathway-based cancer surveillance and treatment strategies.