TP53 polymorphisms

For the most systematic review on TP53 polymorphisms and their functional and clinical consequences, see Whibley et al., 2009. However, please note that this review is not up to date, in particular regarding two variants, V217M (rs35163653) and G360A (rs35993958), that are not frequent SNP based on most recent studies and thus are not considered as validated polymorphisms in the IARC database.

A recent study based on the analysis of large sets of genomic data showed that commonly inherited genetic variants in the p53 pathway affect the incidence of a broad range of cancers more than variants in other pathways (Stracquadanio et al, 2016).

Most of TP53 polymorphisms are located in introns, outside consensus splicing sites. The functional consequences of most of these SNPs is unknown. Theoretically, they may affect p53 protein function through enhanced mutability due to altered DNA sequence context, increased cryptic splicing events, altered transcript stability or translation or tissue-specific expression (Lozano 1991, Mattick 1994). It was shown that the p53 regulatory protein MDM2, that regulate p53 through protein-protein interactions, also binds to p53 mRNA and facilitate its translation. Specific silent mutations in TP53 abrogated this regulation, suggesting that synonymous polymorphisms could affect p53 function through this new mechanism (Candeias, 2008).

A list of variants frequent in healthy human populations, and thus considered as validated polymorphisms in the IARC database, is accessible here.

Among validated polymorphisms, a few have been studied in relation to cancer risk or functional impact. Some knowledge on these polymorphisms is provided here.

  • rs17878362: intron 3 duplication
  • This variant has been found to be associated with increased risk of colorectal cancer in a case-control study and correlated with a reduced level of TP53 mRNA in lymphoblastoid cell-lines (Gemignani 2004). However, because of a strong linkage disequilibrium between the intron 3 duplication and the codon 72 variant, it can not been determined from these experiments whether the intron 3 duplication alone influences mRNA stability or if this effect requires the Pro codon 72 variant. A meta-analysis by Sagne et al., (2013) suggests that rs17878362 is associated with cancer risk, with population and tumour-specific effects. This polymorphism overlaps a G-quadruplex structure that modulate p53 mRNA splicing and stability (Perriaud, 2014).

  • rs1800371: Pro47Ser
  • The P47S variant is a rare polymorphism affecting a codon conserved in evolution. The serine 47 polymorphic variant, which replaces the proline residue necessary for recognition by proline-directed kinases (p38 MAPK), is a markedly poorer substrate for phosphorylation on serine 46 by p38 MAPK. This property correlate with a report that suggested that this polymorphism is functionally significant and show a decrease ability to transactivate two p53 target-genes, p53AIP1 and PUMA, but not other p53 response genes, and to induce apoptosis (Li et al., 2005). A recent study showed that the Pro47Ser variant was not associated with overall breast cancer risk, but may increase risk among pre-menopausal women of African ancestry (Murphy et al., 2017).

  • rs1042522: Pro72Arg
  • Residue 72, although not conserved, is located within the proline-rich region and may affect the structure of the putative SH3-binding domain. Wild-type p53 protein with Arg72 was reported to be more efficient in inducing apoptosis than its Pro variant (Dumont 2003). This property correlated with a greater capacity to interact with MDM2, which facilitate nuclear export and mitochondrial localization. Other differences between the p53 variants have been reported: ability to bind components of the transcriptional machinery, to activate transcription, to induce apoptosis, and to repress the transformation of primary cells (Thomas 1999).
    The protein with Arg72 was also found to be more efficiently targeted for degradation by the E6 protein of HPV16, suggesting that individuals homozygous for Arg72 may be at higher risk of HPV-related cervical cancers (Storey 1998). However, population-based and meta-analysis studies have failed to confirm this hypothesis (Klug 2001, Koushik 2004). 

    Sharp ethnic differences in codon 72 allele frequencies have been observed. In the Northern hemisphere, the Pro72 allele shows a North-South gradient, from 0.17 in Swedish Saamis to 0.63 in African Blacks (Nigerians) (Beckman 1994). In Western Europe (France, Sweden, Norway), North America (USA), Central and South America (Mexico, Costa-Rica, Peru) and Japan, the most common allele is Arg72, with frequencies ranging from 0.60 to 0.83. However, frequencies of Pro72 superior to 0.40 have been observed in African-Americans (Jin 1995, Weston 1992) and in Chineses (Peixoto-Guimaraes 2001, Ngan 1999).
    A study suggest that these latitude-dependent variations may be due to selection related to winter temperature and not to UV radiation as suggested by previous studies. Indeed, Shi et al. (2009) observed that low average temperature, but not UV radiation, was associated with high frequency of Arg72 in Eastern Asia.

    A recent study in mice reported that the P72R Polymorphism of p53 predisposes to besity and metabolic dysfunction (Kung 2016).

    The polymorphic variant at codon 72 has been shown to be an intragenic modifier of mutant p53 behavior (Marin 2000; Basu 2018). Arg72-containing allele was preferentially mutated and retained in squamous cell tumours arising in Arg/Pro germline heterozygotes and was more potent in neutralizing p73-induced apoptosis and cooperating with EJ-Ras to transfrom cells. Other studies in colorectal (Schneider-Stock 2004), lung (Nelson 2005), and head and neck cancers (Schneider-Stock 2004) cancers have aslo found that in Arg/Pro germline heterozygotes, the Pro allele is preferentially lost and the Arg allele is preferentially mutated.

  • rs1794287: intron4, g.7675519A>G (hg38)
  • This SNP was shown by Bellini et al., (2010) to affect the activity of the internal promoter of TP53 controlling the production of dN133p53 isoform.

  • rs78378222 and rs35850753 in untranslated regions
  • These two rare germline variants that are in linkage disequilibrium and map to the 3'-UTR of TP53 and the 5'-UTR of the d133 isoform of TP53, respectively, have been shown to robustly associate with neuroblastoma in various populations (Diskin 2014). rs35850753: odds ratio [OR] = 2.7, 95% confidence interval [CI] = 2.0 to 3.6; rs78378222: OR = 2.3, 95% CI = 1.8 to 2.9.