For the most recent review on TP53 polymorphisms and their functional and clinical consequences, see Whibley et al., 2009.
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).
To view validated polymorphisms (neutral variants frequent in healthy human populations), use the database search.
Among validated polymorphisms, a few have been studied in relation to cancer risk or function impact. Some knowledge on these polymorphisms is provided here.
The P47S (rs1800371) 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 recent report that suggest 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).
Residue 72 is polymorphic (rs1042522). This residue, although not conserved, is located within the proline-rich region and may affect the structure of the putative SH3-binding domain.
The protein with Arg72 was reported to be more efficient in inducing apoptosis than the one with the 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.
The polymorphic variant at codon 72 has been shown to be an intragenic modifier of mutant p53 behavior (Marin 2000). 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.
Many studies have investigated the associations of TP53 polymorphisms with increased risk for cancers. Codon 72 (Arg/Pro), intron 6 (G>A) and intron 3 duplication are the more extensively studied. However, in several cases, putative associations have been challenged by subsequent studies. In lung cancer for example, the codon 72 Pro/Pro genotype has been associated with an elevated risk (Kawajiri 1993, Wu 2002). Another study showed that the Arg/Pro genotype contributes to heritable susceptibility for smoke-induced lung carcinoma (Fan 2000). However, the results were not confirmed in six other case-control studies (Weston 1997). In fact, two meta-analyses have been performed and report different results. One included 13 studies on the above mentioned 3 TP53 polymorphisms and lung cancer risk and failed to found any significant association (Matakidou 2003). Another one included 23 published studies and report that the Pro allele at codon 72 is a low-penetrant risk factor for developing lung cancer, especially in Asians and caucasians, in lung adenocarcinoma, or in smokers (Li 2009). In breast cancer, a large recent study has found that none of the frequent TP53 SNPs were associated with breast cancer risk (Baynes 2007). In ovarian cancer, a pooled analysis of individual data from 49 studies (Klug 2009) did not found any association between cervical cancer and codon 72 polymorphis. Subgroup analyses indicated that excess risks were most likely not due to clinical or biological factors, but to errors in study methods.
The intron 3 duplication (rs17878362) 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. In Wu et al. (2002)), haplotypes (Codon 72 Arg/Pro, intron 6 G>A and intron 3 duplication) were found to be associated with increased lung cancer risk and correlated with higher apoptotic indices and DNA repair capacity in lymphoblastoid cell-lines. These experimental data suggest that these polymorphisms may affect p53 function. A recent meta-analysis including a total of 9801 cases and 10,391 controls from 26 studies (Hu Z, 2010), revealed that the 16 bp insertion (Ins) allele was significantly associated with an increased cancer risk in overall analysis and particularly in the breast cancer subgroup (Ins/Ins versus Del/Del: OR = 1.81, 95% CI = 1.30-2.52, P < 0.001). In another meta-analysis based on case-control studies (He 2011), IVS3 16 bp was reported to be an important genetic marker contributing to susceptibility of breast cancer.
In untranslated regions (UTR), two rare germline variants, rs78378222 and rs35850753 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 recently 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.