p53 polymorphisms: cancer implications

Key Points TP53 , which encodes p53, is a tumour suppressor gene that is frequently mutated in sporadic cancers. The mutations are usually single base substitutions that disrupt function, and some confer new oncogenic (gain-of-function) properties. Over 200 single nucleotide polymorphisms (SNPs; germline variants) in TP53 have been identified; in contrast to tumour-associated mutations, most of these TP53 SNPs are unlikely to have biological effects. Owing to the importance of p53 in tumour suppression, the polymorphisms that alter p53 function might affect cancer risk, progression and/or response to treatment. p53 lies at the hub of a vast signalling network. Polymorphisms in upstream activators, repressors or downstream effectors of p53 might individually modulate cancer risk or interact with polymorphisms or mutations in TP53 . Because the effects of a polymorphism can be subtle and can vary according to genetic background, there are rigorous methodological challenges associated with determining the effect of a polymorphism on cancer risk. Even for the most studied SNP in p53 at codon 72, R72P, the results have been inconsistent, particularly those from population studies that have investigated associations with cancer risk. Population studies require large sample sizes (in the thousands). High-throughput sequencing and the development of genome-wide SNP maps are allowing larger and more comprehensive studies of polymorphisms to be carried out. To date, no study of a sufficient size has reported a significant association between SNPs at the TP53 locus and altered cancer risk. Molecular studies examining the effects of p53 polymorphisms have been based principally on in vitro models with transfected cell lines. The biological effects of p53 pathway variants at the molecular level in primary cells or in vivo still need to be determined. The design of genetically engineered mice using knock-in and knockout technology to study human polymorphisms is currently underway. There are >200 naturally occurring single nucleotide polymorphisms (SNPs) of TP53 in human populations and only a fraction, if any, are expected to perturb p53 function. This Review discusses the evidence linking p53 SNPs with cancer risk and prognosis. The normal functioning of p53 is a potent barrier to cancer. Tumour-associated mutations in TP53 , typically single nucleotide substitutions in the coding sequence, are a hallmark of most human cancers and cause dramatic defects in p53 functio