TP53 Arg72Pro Research Articles

Polymorphisms of the pri-miR-34b/c promoter and TP53 codon 72 are associated with risk of colorectal cancer

The microRNA (miR)-34 family is a direct transcriptional target of tumor-suppressor TP53 and loss of miR-34 function may impair TP53-mediated cell cycle arrest and apoptosis. In the present study, we investigated whether the single nucleotide polymorphisms (SNPs) rs4938723 (T>C) in the promoter region of miR-34b/c and Arg72Pro (G>C) in codon 72 of TP53 are independently or complementarily associated with the risks and clinical outcomes of colorectal cancer (CRC) and whether the combined effect of these SNPs and metabolic risk factors are related to CRC. We evaluated the SNPs in 545 CRC patients and 428 healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequence analysis. We found that the GC and GC/CC genotypes of TP53 Arg72Pro were associated with decreased risk of CRC (adjusted OR = 0.727 for GC; OR = 0.735 for GC/CC). The combined genotypes of TT-GC and CC-GG were significantly associated with reduced CRC risk (adjusted OR = 0.628 for TT-GC; OR = 0.381 for CC-GG, respectively). The SNP rs4938723 and diabetes mellitus (DM) together were associated with an increased CRC risk, but the SNP TP53 Arg72Pro CC with DM showed a protective effect against CRC. These findings indicate that rs4938723 in the promoter region of pri-miR-34b/c and the SNP in TP53 codon 72 were related to decreased risk of CRC in the population studied and those metabolic diseases and genetic variants influence each other with regard to CRC susceptibility.

Arg72Pro Polymorphism of TP53 Gene and the Risk of Skin Cancer: a Meta-Analysis

Background TP53 gene is one of the most important tumor suppressor genes. We undertook this meta-analysis to explore the association between TP53 Arg72Pro polymorphism and the risk of skin cancer mainly in Caucasians.MethodsWe searched PubMed for case-control studies published up to March 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association.ResultsA total of 5276 skin cancer cases and 5315 controls from 20 studies were included. Overall, no significant association between TP53 Arg72Pro polymorphism and skin cancer was observed in all genetic contrast models (Pro/Pro versus Arg/Arg, Pro/Arg versus Arg/Arg, Pro/Pro + Pro/Arg versus Arg/Arg, Pro/Pro versus Arg/Arg + Pro/Arg, Pro allele versus Arg allele). Similar results were obtained in the stratified analysis by ethnicity and histological types of skin cancer, such as melanoma, squamous cell carcinoma and basal cell carcinoma. Power calculations indicated that some studies were underpowered. No publication bias was found by using the funnel plot and Egger's test.ConclusionsThis meta-analysis indicated that TP53 Arg72Pro polymorphism probably had little association with skin cancer susceptibility mainly in Caucasians. However, larger sample-size studies are required to verify the conclusion as low statistical powers.

RAD51 135G>C and TP53 Arg72Pro polymorphisms and susceptibility to breast cancer in Serbian women

Breast cancer is a complex disease with both genetic and environmental factors involved in its etiology. An important role of polymorphisms in genes involved in DNA repair has been reported related to breast cancer risk. We conducted a case-control study in order to investigate the association of RAD51 135G>C and TP53 Arg72Pro polymorphisms with breast cancer in Serbian women.48 BRCA negative women with breast cancer and family history of breast/ovarian cancer (hereditary group), 107 women with breast cancer but without family history of the disease (sporadic group) and 114 healthy women without a history of the disease (control group) were included. Restriction fragment length polymorphism was used for genotyping. Genotype and allelic frequencies, the odds ratio (OR) and the 95% confidence interval (CI) were calculated as an estimate of relative risk. The Hardy-Weinberg equilibrium was tested using χ(2) test. Significance was considered for p<0.05. RAD51 135G>C showed statistically significant association of CC genotype and increased breast cancer risk (OR 10.28, 95% CI 1.12-94.5) in hereditary group of patients compared to the control group. Regarding the TP53 Arg72Pro, we showed statistical significance for ProPro+ProArg comparing to ArgArg (OR 2.34, 95%, CI 1.17-4.70) in hereditary compared to sporadic group. RAD51 135G>C contributes to hereditary breast cancer in Serbian population, with CC genotype as a risk factor. We also found that carriers of Pro allele of TP53 codon 72 is related to hereditary cancer comparing to sporadic one, which indicates it as a potential risk factor for hereditary form of disease.

Quantitative assessment of the association between TP53 Arg72Pro polymorphism and risk of glioma

Many studies have investigated on the association between TP53 Arg72Pro polymorphism and risk of glioma, but the impact of TP53 Arg72Pro polymorphism on glioma risk is unclear owing to the obvious inconsistence among those studies. To shed light on these inconclusive findings and get a quantitative assessment of the association between the TP53 Arg72Pro polymorphism and risk of glioma, we conducted a meta-analysis of eligible studies. We searched PubMed and Embase databases for studies investigating on the association between the TP53 Arg72Pro polymorphism and risk of glioma. The pooled odds ratios (OR) with their 95% confidence intervals (95% CI) was calculated to assess the association between the TP53 Arg72Pro polymorphism and risk of glioma. A total of 12 studies were finally included into the meta-analysis. Meta-analysis of the 12 studies showed that TP53 Arg72Pro polymorphism was not associated with the risk of glioma (OR(Pro vs. Arg) = 1.07, 95% CI 0.93∼1.22; OR(ProPro vs. ArgArg) = 1.02, 95% CI 0.85∼1.22; OR(ProPro/ArgPro vs. ArgArg )= 1.06, 95% CI 0.85∼1.34; and OR(ProPro vs. ArgArg/ArgPro) = 1.07, 95% CI 0.91∼1.27). Subgroup analyses by ethnicity further identified that TP53 Arg72Pro polymorphism was not associated with the risk of glioma in Caucasians. However, there was a mild association between the TP53 Arg72Pro polymorphism and risk of glioma in Asians (OR(ProPro vs. ArgArg/ArgPro) = 1.42, 95% CI 1.00∼2.02). Thus, there is limited evidence for the association between the TP53 Arg72Pro polymorphism and risk of glioma, and more studies are needed to provide a more comprehensive assessment of the association in Asians.

Polymorphisms in the p27 kip-1 and prohibitin genes denote novel genes associated with melanoma risk in Brazil, a high ultraviolet index region

Ultraviolet (UV) radiation is a major environmental risk factor to the development of cutaneous melanoma as it induces pyrimidine dimers in DNA. Genes that exert their function by arresting the cell cycle are critical to avoid carcinogenic mutations, allowing the processing of DNA repair systems. This study was carried out to evaluate the role of polymorphisms in cell cycle genes such as TP53, p27, CDKN2A, prohibitin, and GADD153 in melanoma risk as well as their influence on known risk factors in a high UV index region. A hospital-based case-control study was carried out in Brazil to evaluate the contribution of polymorphisms in cell cycle genes toward melanoma risk. The study comprised 202 melanoma patients and 210 controls. The polymorphisms analyzed were TP53 Arg72Pro, p27 Val109Gly, GADD153 Phe10Phe (rs697221), CDKN2A 3'UTR C540G, and prohibitin 3'UTR C1703T. As regards, p27 Val109Gly, both heterozygous and homozygous Gly genotypes were shown to be protective genotypes on calculating both crude and adjusted odds ratios (ORs) for age, sex, and educational level [OR 0.37; 95% confidence interval (CI) 0.16-0.87; P<0.05]. Similarly, the prohibitin TT genotype increased melanoma risk in the crude and adjusted analyses (OR 2.40; 95% CI 1.10-5.26; P<0.05). The p27 Gly protective genotype decreased the risk for melanoma in a stratified analysis of the known risk factors such as hair and eye color, sunburns, pigmented lesions, and European ancestry. The prohibitin TT genotype increased the risk of melanoma by such host factors. Our results showed for the first time that polymorphisms in p27 Val109Gly and in prohibitin 3'UTR C1703T genotypes modulate the risk to melanoma in a high UV index region.

Genotype Misclassification in Genetic Association Studies of the rs1042522 TP53 (Arg72Pro) Polymorphism: A Systematic Review of Studies of Breast, Lung, Colorectal, Ovarian, and Endometrial Cancer

Preferential loss of heterozygosity at the rs1042522 locus of the tumor protein 53 gene (TP53) (Arg72Pro) is observed in several tumors. Genetic association studies in oncology often use tumor tissue rather than unaffected tissue for genotyping; in such cases, loss of heterozygosity at the TP53 locus could lead to differential misclassification and could bias estimates of association. We searched multiple databases (through March 8, 2011) for studies investigating the association of Arg72Pro with breast, lung, colorectal, ovarian, or endometrial cancer. Meta-analysis was performed with multilevel Bayesian models. Informative priors for the bias effect were derived from a meta-analysis of the same polymorphism in cervical cancer. Of 160 studies (68 breast, 42 lung, 26 colorectal, 16 ovarian, and 8 endometrial cancer), 22 used tumor tissue as the source of genotyping material for cases. Use of tumor tissue versus other sources of genotyping material was associated with an apparent protective effect of the proline allele (relative odds ratio = 0.78, 95% credible interval: 0.70, 0.88). The probability that use of tumor tissue induced bias was estimated to be higher than 99%. Use of tumor tissue as the source of genotyping material for cases is associated with significant bias in the estimate of the genetic effect in cancer genetic association studies.

The prognostic role of XRCC1, ERCC1, ERCC2, and TP53 single nucleotide polymorphisms (SNPs) in resected non-small cell lung cancer (NSCLC).

e18521 Background: Identification of biomarkers that can be used for the prognostic evaluation of NSCLC patients is important. The aim of this study was to evaluate the potential prognostic value of XRCC1, ERCC1, ERCC2 and, TP53 SNPs in completely resected NSCLC patients. Methods: In total 130 patients, who had been surgically treated for NSCLC between 2000 and 2012, were included in this study. Analysis of SNPs from peripheral blood cells was performed by polymerase chain reaction. XRCC1 Arg399Gln, ERCC1 Asn118Asn, ERCC2 Lys751Gln and, TP53 Arg72Pro polymorphisms were evaluated in conjunction with clinical and pathological parameters and survival. Kaplan-Meier method and Cox regression analysis were used. Results: In the univariate analysis for disease free survival (DFS) post operative stage (HR,0.50; 95%CI, 0.26-0.96; P=0.03), ERCC2 genotype (HR, 2.47; 95%CI, 1.28-4.78; P=0.007) and PET-CT staging (HR, 0.27;95%CI, 0.14-0.52; P&lt;0.001) were significant parameters. Adjuvant chemotherapy, age and the other SNPs were not significant. In the multivariate analysis post operative stage (HR, 0.40;95%CI, 0.20-0.81; P=0.01), ERCC2 genotype (HR, 2.66;95%CI, 1.35-5.27; P=0.005), PET-CT staging (HR, 0.24;95%CI, 0.12-0.47; P&lt;0.001) retained their significance. The median DFS was 56.5 months (95%CI, 24.6-88.4 months) for the ERCC2 mutant (TT) and heterozygote (GT) genotypes, and 28.3 months (95%CI, 20.8-35.8 months) for the ERCC2 normal (GG) genotype (P=0.005). Conclusions: In addition to stage and PET-CT staging, ERCC2 genotype independently predicted DFS in resected NSCLC patients. Future prospective studies are needed for the further evaluation of potential prognostic SNPs in resected NSCLC.

Association of MDM2 SNP309 and TP53 Arg72Pro polymorphisms with risk of endometrial cancer

The incidence of endometrial cancer, a common gynecological malignancy, is increasing in Japan. We have previously shown that the ER/MDM2/p53/p21 pathway plays an important role in endometrial carcinogenesis. In the present study, we investigated the effects of germline single nucleotide polymorphisms in murine double minute 2 (MDM2) SNP309, TP53 Arg72Pro, ESR1 PvuII and XbaI, and p21 codon 31 on endometrial cancer risk. We evaluated these polymorphisms in DNA samples from 125 endometrial cancer cases and 200 controls using polymerase chain reaction-based restriction fragment length polymorphism. The association of each genetic polymorphism with endometrial cancer was examined by the odds ratio and 95% confidence interval, which were obtained using logistic regression analysis. The SNP309 GG genotype non-significantly increased the risk of endometrial cancer. The 95% confidence interval for the GG genotype vs. the TT genotype of MDM2 SNP309 was 1.76 (0.93–3.30). Endometrial cancer was not associated with tested SNP genotypes for TP53, ESR1 and p21. The combination of SNP309 GG + TG and TP53 codon 72 Arg/Arg significantly increased endometrial cancer risk. The adjusted OR was 2.53 (95% confidence interval, 1.03–6.21) and P for the interaction was 0.04. This result was supported by in vitro data showing that endometrial cancer cell lines with the SNP309 G allele failed to show growth inhibition by treatment with RITA, which reduces p53-MDM2 binding. The presence of the SNP309 G allele and TP53 codon 72 Arg/Arg genotype is associated with an increased risk of endometrial cancer in Japanese women.

Promoter polymorphisms of pri-miR-34b/c are associated with hepatocellular carcinoma

BackgroundNumerous studies have focused on the association between miR-34 family members, which are direct p53 targets, and carcinogenesis of many cancers, including hepatocellular carcinoma (HCC). This study aimed to assess whether polymorphisms in the single-nucleotide polymorphism miR-34b/c T>C (rs4938723) and TP53 Arg72Pro (rs1042522) increase the risk of HCC and influence outcome in patients with HCC. Patients and methodsWe enrolled 157 HCC patients and 201 cancer-free control subjects from the Korean population. MicroRNA polymorphisms were genotyped using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method. ResultsWe found that the miR-34b/c TC+CC frequency was significantly higher in HCC patients than in controls (adjusted odds ratio [AOR]: 1.580; 95% confidence interval [CI]: 1.029–2.426). The miR-34b/c CC-TP53 Arg/Arg combination significantly increased the risk of HCC (AOR: 13.644; 95% CI: 1.451–128.301). The SNPs miR-34b/c T>C and TP53 Arg72Pro(G>C) had no influence on survival of HCC patients. ConclusionsOur findings suggest that loss of the T allele in miR-34b/c T>C, and the miR-34b/c CC-TP53 Arg/Arg combination increases the risk of HCC in the Korean population.

The Association Between TP53 Arg72Pro Polymorphism and Lung Cancer Susceptibility: Evidence from 30,038 Subjects

The TP53 codon 72 polymorphism has been associated with the individual susceptibility to lung cancer. However, the association remains uncertain and varies with ethnicity, smoking status, cancer histology, and stage. We performed a meta-analysis to evaluate the relationship between TP53 Arg72Pro polymorphism and lung cancer susceptibility basing on 15,647 lung cancer patients and 14,391 controls from 36 published literatures. We also performed stratified analysis in populations of different ethnicities, smoking statuses, lung cancer stages, and histological types. The analysis showed a significantly increased lung cancer susceptibility among Pro allele carriers (P < 0.001, odds ratio (OR) = 1.14, 95% confidence interval (CI) = 1.1-1.19), especially for smokers (P < 0.001, OR = 1.29, 95% CI = 1.12-1.47). Stratified analysis indicated that Pro72 elevates lung cancer susceptibility in Asians, while it has no effect on lung cancer risk of Caucasians. Moreover, Pro carriers present an increased risk of developing squamous cell carcinoma and adenocarcinoma, instead of large cell carcinoma and small cell carcinoma. Interestingly, patients with the Pro allele seemed to be diagnosed with lung cancer at the early stages (stage I-II, P = 0.008, OR = 1.2, 95% CI = 1.05-1.37). Our results suggest that the Pro allele acts as a risk factor for development of lung cancer, especially for smokers and Asians.

Abstract 3063: MicroRNA-605: A novel genetic modifier in Li-Fraumeni Syndrome.

Abstract Background: Li-Fraumeni syndrome (LFS) is a rare autosomal-dominant disorder, typically involving germ-line mutations in the prototypical tumour suppressor gene, TP53. Despite the high penetrance of TP53 mutations, LFS patients display striking differences in the age of disease onset, suggesting the presence of additional genetic modifiers. To date, functional polymorphisms in TP53 (Arg72Pro), MDM2 (SNP 309), as well as DNA copy number variations (CNVs) and telomere attrition, have been associated with cancer risk in LFS. However, it is likely that additional modifiers exist and that a combination of these low-penetrance risk factors act together to predispose TP53 mutation carriers to a spectrum of susceptibilities. Recently, the TP53 signalling network has been linked to a small number of non-coding RNAs, called microRNAs (miRNAs), whose main function is to negatively regulate gene expression. One particular member of this family, called miR-605, has been found to target the MDM2 gene, an important inhibitor of p53 function. Importantly, a common Single Nucleotide Polymorphism (SNP) within miR-605 was also found to modulate gastrointestinal cancer risk. By affecting miR-605 expression, this SNP could impact cancer risk in TP53 mutation carriers. Hypothesis: In this study, we hypothesized that SNP-mediated miR-605 deregulation might modify cancer risk in LFS by eliciting important transcriptional changes in the levels of p53 and/or MDM2. Methods: miR-605 was overexpressed in two TP53 mutant cell lines (RD and Rh30) in order to assess its tumor suppressive functions. MDM2 and TP53 protein expression were analyzed through Western Blotting. Additionally, blood-derived DNA samples from 47 Caucasian TP53 mutation carriers were genotyped for the miR-605 variant by SNP-RFLP. Results: Overexpressing miR-605 in two TP53 mutated cell lines led to a significant attenuation in cell viability as measured by MTS assay. The capacity of these cell lines to form macroscopic colonies was also compromised following transfection by a miR-605 commercial mimic. Moreover, miR-605-transfected cells also displayed higher sensitivity to a wide range of chemotherapeutic drugs. In RD cells, MDM2 downregulation was detected following miR-605 overexpression but TP53 levels remained unchanged. Genotyping our aforementioned study population revealed the G-allele of the miR-605 SNP to be associated with an earlier age of cancer onset (p=0.02). The median age of cancer onset in carriers of the G-allele (n= 15) was 3.75 years compared to 21.5 years in patients with the common homozygous A/A genotype (n= 32). Conclusion: Together, our results identify miR-605 deregulation as a potential cancer modifying event in TP53 mutation carriers. Future work will focus on elucidating the functional consequences of the miR-605 SNP whilst also pursuing a more general understanding of miR-605 tumor suppression. Citation Format: Badr Idsaid, David Malkin. MicroRNA-605: A novel genetic modifier in Li-Fraumeni Syndrome. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3063. doi:10.1158/1538-7445.AM2013-3063

Assessment of the XPC (A2920C), XPF (T30028C), TP53 (Arg72Pro) and GSTP1 (Ile105Val) polymorphisms in the risk of cutaneous melanoma

We examined the influence of XPC A2920C, XPF T30028C, TP53 Arg72Pro and GSTP1 Ile105Val polymorphisms in the risk of cutaneous melanoma (CM). DNA from 146 CM patients and 146 controls was analysed by polymerase chain reaction (PCR)--restriction fragment length polymorphism (RFLP). The frequencies of XPC CC (15.1 vs. 6.9 %, P = 0.02), TP53 ArgArg (59.6 vs. 45.9 %, P = 0.02), XPC CC plus TP53 ArgArg (19.7 vs. 5.2 %, P = 0.01) and TP53 ArgArg plus GSTP1 IleIle (50.7 vs. 35.6 %, P = 0.03) genotypes were higher in patients than in controls. Carriers of the respective genotypes were under a 2.51 (95 % CI: 1.13-5.55), 1.76 (95 % CI: 1.09-2.83), 4.52 (95 % CI: 1.35-15.16), and 2.01 (95 % CI: 1.04-3.90)-fold increased risks for CM than others, respectively. An excess of TP53 ArgArg genotype was seen in patients with excessive sun exposure compared to patients with standard sun exposure (69.2 vs. 44.1 %, P = 0.02) and also compared to controls (69.2 vs. 45.9 %, P = 0.002). Individuals with TP53 ArgArg genotype and highly exposed to sunlight had 2.65 (95 % CI: 1.42-4.92)-fold increased risk for CM than others. XPC CC (27.8 vs. 10.4 %, P = 0.02) and the GSTP1 IleIle (58.3 vs. 36.8 %, P = 0.04) genotypes were more common in patients with advanced tumours than in patients with localized tumours and were also more common in these patients than in controls (27.8 vs. 6.9 %, P = 0.001; 58.3 vs. 37.0 %, P = 0.02, respectively). Individuals with the respective genotypes had 5.23 (95 % CI: 1.97-13.82)-fold and 2.38 (95 % CI: 1.13-5.01)-fold increased risks for advanced tumour than others, respectively. Our data suggest that inherited abnormalities of XPC, XPF, TP53 and GSTP1 pathways of the DNA repair, apoptosis and metabolism of reactive oxygen species are important determinants of CM in individuals from south-eastern Brazil.

Interactions of miR-34b/c and TP-53 polymorphisms on the risk of nasopharyngeal carcinoma

Growing evidence indicates that tumor suppressor gene TP-53 and non-coding RNA miR-34b/c independently and/or jointly play crucial roles in carcinogenesis. We hypothesized that the polymorphisms of rs4938723 in the promoter region of pri-miR-34b/c and TP-53 Arg72-Pro may be related to the risk of nasopharyngeal carcinoma (NPC). We performed a case-control study between 217 patients with NPC and 360 healthy controls in a Chinese population using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. A significantly increased risk of NPC was observed in the miR-34b/c rs4938723 CT/CC genotypes compared with the TT genotype (adjusted OR=1.44, 95 % CI 1.02-2.03, p=0.04), and also the C allele (adjusted OR=1.33, 95 % CI 1.04-1.70, p=0.03). The gene-gene interaction of miR-34b/c rs4938723 and TP-53 Arg72-Pro showed that the combined genotypes of rs4938723CT/CC and TP-53CG/CC increased the risk of NPC (rs4938723CT/CC + TP-53CG/CC vs. rs4938723 TT+TP-53 CG/CC: OR=1.58, 95 % CI 1.04-2.42, p=0.03). These findings suggest that miR-34b/c rs4938723 and TP-53 Arg72Pro polymorphisms may singly or collaboratively contribute to the risk of NPC.

Effect of TP53 codon 72 and MDM2 SNP309 polymorphisms on survival of gastric cancer among patients who receiving 5-fluorouracil-based postoperative adjuvant chemotherapy

Several studies have examined the prognostic value of the TP53 Arg72Pro polymorphism (rs1042522) and/or MDM2 SNP309 (rs2279744) in multiple tumors. Our aim was to determine whether these two genetic variants were correlated with clinical outcome of gastric cancer. We genotyped the two SNPs, TP53 codon 72 polymorphism and MDM2 SNP309, in 940 gastric cancer patients with complete follow-up information and analyzed the correlation between the SNPs and gastric cancer survival. The two SNPs were not significantly associated with gastric cancer survival. However, the TP53 codon 72 polymorphism had a prominent correlation with clinical outcome of patients receiving 5-fluorouracil (5-Fu)-based postoperative chemotherapy [Arg/Arg + Arg/Pro vs. Pro/Pro, adjusted hazard ratio (HR) = 1.63, 95 % confidence interval (CI) = 1.08-2.44]. Moreover, the unfavorable effect of Arg allele on survival outcome was more predominant for subgroups of older (age >60 years), male, intestinal histology type, advanced stage (T3/T4), and none metastasis of lymph node (N0) or distant (M0) (adjusted HR = 2.34, 95 % CI = 1.24-4.44 for age >60 years; 1.72, 1.10-2.69 for male; 2.30, 1.10-4.80 for intestinal; 1.62, 1.01-2.59 for T3/T4; 3.42, 1.26-9.24 for N0; and 1.62, 1.06-2.47 for M0). Among multiple chemotherapy regimens, the association was only significant in the subgroup of 5-Fu/calcium folinate plus oxaliplatin (FOLFOX) chemotherapy regimen (adjusted HR = 4.47, 95 % CI = 1.21-16.55). Our findings showed that TP53 codon 72 polymorphism was associated with survival of gastric cancer patients treated with 5-Fu-based postoperative chemotherapy. The codon 72 polymorphism may be a potential prognostic factor.

A genetic variant in the promoter region of miR-34b/c is associated with a reduced risk of colorectal cancer

The miR-34 family members, described as potential tumor suppressors, were downregulated in colorectal cancer (CRC). Loss of miR-34 impairs TP53-mediated cell death, while overexpression of miR-34 induces apoptosis. A potentially functional polymorphism (i.e., rs4938723T/C) in the promoter region of pri-miR-34b/c was predicted to influence the GATA-X binding sites. We aimed to investigate the association between miR-34b/c rs4938723 and TP53 Arg72Pro polymorphisms and the risk of CRC. We genotyped the two polymorphisms in 347 CRC patients and 488 healthy controls using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing assay. We found that the CC genotype and C allele of the miR-34b/c rs4938723 were associated with a significantly decreased risk of CRC compared with the TT genotype and T allele (CC vs. TT: adjusted OR=0.56; 95% CI, 0.34-0.91; C vs. T: adjusted OR=0.78; 95% CI, 0.64-0.97). In combined analysis, a borderline significance was also observed in subjects carrying the rs4938723 CT/CC and TP53 GG genotypes (adjusted OR=0.66; 95% CI, 0.43-0.99). These findings indicate that the rs4938723 in the promoter region of pri-miR-34b/c was a protective factor for the development of CRC. As the significance is marginal, further replication studies are warranted to confirm these results.

The association between TP53 Arg72pro polymorphism and non-melanoma skin cancer risk: A meta-analysis including 7,107 subjects

Background:The p53 gene is a critical molecular in the protection of cells from DNA damage due to Ultraviolet (UV) exposure, and TP53 mutation is very common in non-melanoma skin cancer.Objectives:To assess the association between the TP53 Arg72Pro polymorphism and non-melanoma skin cancer (NMSC) risk.Methods:We performed this meta–analysis with 13 case-control studies involving 3,520 cases and 3,587 controls.Results:Our meta-analysis showed that TP53 Arg72Pro polymorphism was not associated with non-melanoma skin cancer susceptibility in overall population.(for Arg/Arg vs. Pro/Pro: OR 0.98, 95% CI 0.80-1.19; for Arg/Pro vs. Pro/Pro: OR 0.99, 95% CI 0.84-1.17; for the recessive model Arg/Arg vs. Arg/Pro + Pro/Pro: OR 1.10, 95% CI 0.89-1.35; for the dominant model Arg/Arg + Arg/Pro vs. Pro/Pro: OR 1.00, 95% CI 0.85-1.18). We also detected no effect of this polymorphism on any subtype of non-melanoma skin cancer, such as squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). Furthermore, no significant association in any subgroup was detected in stratified analyses according to ethnicity. However, in the stratified analysis by sample collection resources, Arg/Arg carriers from tumor tissue subgroup had 3.42 times risk of cancer (95% CI, 1.19 to 9.84) as compared with the variant type Pro/Pro in NMSC.Conclusions:TP53 Arg72Pro polymorphism may have little involvement in the pathogenesis of NMSC, regardless of type, including SCC, and BCC.

Quantitative assessment of the association between TP53 Arg72Pro polymorphism and bladder cancer risk

Previous studies investigating the association between TP53 Arg72Pro polymorphism and bladder cancer risk reported controversial results. To quantify the strength of association between TP53 Arg72Pro polymorphism and bladder cancer risk, we performed this meta-analysis. We searched PubMed, Embase and Wangfang databases for studies relating the association between TP53 Arg72Pro polymorphism and bladder cancer risk. We used the pooled odds ratios (ORs) with their 95 % confidence intervals (95 % CIs) to assess the association. Finally, data were available from a total of 16 case-control studies including a total of 5, 545 subjects (2,345 cases and 3,200 controls). Meta-analysis of all 16 studies showed TP53 Arg72Pro polymorphism was not associated with bladder cancer risk (All P values were more than 0.10). Subgroup analyses by ethnicity showed that TP53 Arg72Pro polymorphism contributed to bladder cancer risk in East Asians in three genetic models (For Pro vs. Arg, Fixed-effects OR 1.18, 95 % CI 1.05-1.32; For ProPro vs. ArgArg, Fixed-effects OR 1.40, 95 % CI 1.11-1.77; For ProPro vs. ArgPro/ArgArg, Fixed-effects OR 1.32, 95 % CI 1.07-1.62). However, there was no significant association in Caucasians and the others (All P values were more than 0.05). Heterogeneity analyses suggested ethnicity was the major sources of heterogeneity. Thus, meta-analyses of available data suggest the Pro variant of TP53 Arg72Pro contributes to bladder cancer risk in East Asians. Besides, TP53 Arg72Pro polymorphism may have race-specific effects on bladder cancer risk and further studies are needed to elucidate this possible effect.

Association of p21 Ser31Arg and p53 Arg72Pro polymorphisms with lung cancer risk in CAPUA study.

The aim of this study was to investigate how Ser31Arg polymorphisms in p21 may modify lung cancer susceptibility. Because p21 is the major downstream mediator of p53, we analyzed the combined effect of two polymorphisms, p21 Ser31Arg and TP53 Arg72Pro, to elucidate whether polymorphic variants determine the risk of lung cancer. This was designed as a hospital-based case-control study, and included 675 cases and 675 control subjects matched by ethnicity, gender, and age. Genotypes were determined by polymerase chain reaction restriction fragment length polymorphism, and multivariate unconditional logistic regression was performed to analyze the results. Subjects who carried the p21 Ser31Arg allele had a higher risk of lung cancer (adjusted odds ratio [OR] 1.38; 95% confidence interval [CI] 0.99-2.03). This risk was increased in men aged younger than 55 years (adjusted OR 2.35; 95% CI 1.00-5.51). Smokers had an increased risk of lung cancer (adjusted OR 2.23; 95% CI 1.24-4.02). Men younger than 55 years carrying risk alleles for both genes (p21 Ser31Arg and TP53 Arg72Pro) had an increased risk (adjusted OR 5.78; 95% CI 1.38-24.19), as did smokers with both risk alleles (adjusted OR 4.52; 95% CI 1.52-13.50). The presence of both variant alleles increased the risk of developing lung cancer in men, particularly in smokers younger than 55 years.

The Pro Allele of the p53 Codon 72 Polymorphism Is Associated with Decreased Intratumoral Expression of BAX and p21, and Increased Breast Cancer Risk

BackgroundThe TP53 Arg72Pro polymorphism encodes two p53 variants with different biochemical properties. Here we investigated the impact of this polymorphism on the expression of key p53 target genes in a panel of human breast carcinomas, breast cancer risk, and age at onset.Methodology/Principal FindingsThe Arg72Pro polymorphism was genotyped in 270 breast cancer patients and 221 control subjects. In addition, the Arg72Pro genotype of 116 breast tumors was determined, and correlated with intratumoral mRNA expression of TP53 and its key target genes MDM2, p21, BAX, and PERP, as quantified by qRT-PCR. We found a significantly increased breast cancer risk associated with the Pro-allele (per-allele odds ratio, 1.46; 95% confidence interval, 1.08–1.99), and a significantly later mean age at breast cancer onset for Pro/Pro patients (63.2±18 years) compared to Arg/Arg patients (58.2±15 years). The frequency of somatic TP53 inactivation was 25.4% in Arg/Arg, 20.9% in Arg/Pro, and 16.7% in Pro/Pro patients, which may reflect a higher selective pressure to mutate the Arg-allele. The median mRNA levels of p21 and BAX in the tumors of Pro-allele carriers were significantly reduced to 55.7% and 76.9% compared to Arg/Arg patients, whereas p53, MDM2 and PERP expression were hardly altered.Conclusions/SignificanceThe p5372Arg variant appears to be a more potent in vivo transcription factor and tumor suppressor in human breast cancer than the p5372Pro variant. The Arg72Pro genotype has no significant effects in patients with TP53 mutated tumors, in which p53 is non-functional.

Association Between TP53 Arg72Pro Polymorphism and Hepatocellular Carcinoma Risk: A Meta-analysis

Previous studies on the association between the TP53 Arg72Pro polymorphism and hepatocellular carcinoma (HCC) risk obtained controversial findings. This study aimed to quantify the strength of the association by meta-analysis. We searched PubMed and Wangfang databases for published studies on the association between the TP53 Arg72Pro polymorphism and HCC risk, using the pooled odds ratio (OR) with its 95% confidence intervals (95% CI) for assessment. 10 studies with a total of 2,026 cases and 2,733 controls were finally included into this meta-analysis. Overall, the TP53 Arg72Pro polymorphism was not associated with HCC risk (all P values greaterth HCC risk in Caucasians in three genetic models (For Pro versus Arg, OR = 1.20, 95%CI 1.03-1.41; For ProPro versus ArgArg, OR = 1.74, 95%CI 1.23-2.47; For ProPro versus ArgPro/ArgArg, OR = 1.85, 95%CI 1.33-2.57). However, there was no significant association between the TP53 Arg72Pro polymorphism and HCC risk in East Asians (all P values greater than 0.10). No evidence of publication bias was observed. Meta-analyses of available data suggest an obvious association between the TP53 Arg72Pro and HCC risk in Caucasians. However, the TP53 Arg72Pro polymorphism may have a race-specific effect on HCC risk and further studies are needed to elucidate this possible effect.