Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Jul 19;11(7):578-585.
doi: 10.1093/jmcb/mjz052.

Common genetic variants in the TP53 pathway and their impact on cancer

Thibaut Barnoud  1 , Joshua L D Parris  1   2 , Maureen E Murphy  1
Affiliations
Review

Common genetic variants in the TP53 pathway and their impact on cancer

Thibaut Barnoud et al. J Mol Cell Biol. .

Abstract

The TP53 gene is well known to be the most frequently mutated gene in human cancer. In addition to mutations, there are > 20 different coding region single-nucleotide polymorphisms (SNPs) in the TP53 gene, as well as SNPs in MDM2, the negative regulator of p53. Several of these SNPs are known to alter p53 pathway function. This makes p53 rather unique among cancer-critical genes, e.g. the coding regions of other cancer-critical genes like Ha-Ras, RB, and PI3KCA do not have non-synonymous coding region SNPs that alter their function in cancer. The next frontier in p53 biology will consist of probing which of these coding region SNPs are moderately or strongly pathogenic and whether they influence cancer risk and the efficacy of cancer therapy. The challenge after that will consist of determining whether we can tailor chemotherapy to correct the defects for each of these variants. Here we review the SNPs in TP53 and MDM2 that show the most significant impact on cancer and other diseases. We also propose avenues for how this information can be used to better inform personalized medicine approaches to cancer and other diseases.

Keywords: MDM2; PAS; Pro47Ser; Pro72Arg; SNP309; p53.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Models of TP53 pathway SNPs and their contributions to cancer. (A) The role of SNP285 and SNP309 on MDM2 expression. While SNP309 promotes binding for the Sp1 transcription factor, SNP285 leads to decreased Sp1 binding and serves to balance the impact of SNP309. (B) Localization of p53 SNPs within the functional domains of p53. The SNP rs1800371 (Pro47Ser) is localized to the TAD2; SNP rs1042522 (Pro72Arg) is localized to the PRD; and SNP rs78378222 is localized to the PAS within the 3′-UTR. TAD, transactivation domain; PRD, proline-rich domain; TD, tetramerization domain; CRD, carboxy-terminal regulatory domain; PAS, polyadenylation signal.
See this image and copyright information in PMC

References

    1. Arva N.C., Gopen T.R., Talbott K.E., et al. (2005). A chromatin-associated and transcriptionally inactive p53-Mdm2 complex occurs in mdm2 SNP309 homozygous cells. J. Biol. Chem. 280, 26776–26787. - PubMed
    1. Asomaning K., Reid A.E., Zhou W., et al. (2008). MDM2 promoter polymorphism and pancreatic cancer risk and prognosis. Clin. Cancer Res. 14, 4010–4015. - PubMed
    1. Atwal G.S., Rabadan R., Lozano G., et al. (2008). An information-theoretic analysis of genetics, gender and age in cancer patients. PLoS One 3, e1951. - PMC - PubMed
    1. Barnoud T., Budina-Kolomets A., Basu S., et al. (2018). Tailoring chemotherapy for the African-centric S47 variant of TP53. Cancer Res. 78, 5694–5705. - PMC - PubMed
    1. Barnoud T., Parris J.L.D., and Murphy M.E. (2019). Tumor cells containing the African-centric S47 variant of TP53 show increased Warburg metabolism. Oncotarget 10, 1217–1223. - PMC - PubMed

Publication types

MeSH terms