Key Points
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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.
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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.
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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.
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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.
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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.
Abstract
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 function. By contrast, only a small fraction, if any, of the >200 naturally occurring sequence variations (single nucleotide polymorphisms, SNPs) of TP53 in human populations are expected to cause measurable perturbation of p53 function. Polymorphisms in the TP53 locus that might have cancer-related phenotypical manifestations are the subject of this Review. Polymorphic variants of other genes in the p53 pathway, such as MDM2, which might have biological consequences either individually or in combination with p53 variants are also discussed.
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Acknowledgements
The Hollstein laboratory is funded by Yorkshire Cancer Research and Cancer Research UK. Discussions and comments from M. Murphy, L. Hardie, P. Stambrook and T. Hupp are gratefully acknowledged.
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DATABASES
OMIM
FURTHER INFORMATION
Database of germline p53 mutations
Glossary
- Polymorphism
-
A germline variation within a gene (often at a single nucleotide, known as single nucleotide polymorphisms, SNPs) that exists at a frequency of at least 1% in the general population.
- Penetrance
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A measure of the proportion of genetically similar individuals that show any phenotypical manifestation of a mutation that they have in common.
- p53 response element
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A short sequence of DNA in or near a gene that can bind p53, which then regulates the transcriptional activity of that gene.
- p53 family
-
This family includes p53, p63 and p73, which have a significant degree of sequence homology particularly in the sequence-specific DNA-binding domain.
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Whibley, C., Pharoah, P. & Hollstein, M. p53 polymorphisms: cancer implications. Nat Rev Cancer 9, 95–107 (2009). https://doi.org/10.1038/nrc2584
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DOI: https://doi.org/10.1038/nrc2584
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