Association of Arg72Pro of TP53 and T309G of MDM2 genes polymorphisms with non-small-cell lung cancer in Russians of the Moscow region

Association of TP53 Arg72Pro and MDM2 T309G polymorphic markers with the risk of non-small-cell lung cancer was studied in a Russian population of the Moscow region. The minor Pro/Pro genotype of Arg72Pro and the TG genotype of T309G were associated with non-small-cell lung cancer (OR = 5.46, p = 8 × 10^?6 and OR = 7.38, p = 0.0001, respectively). Both Pro/Pro and TG genotypes were also strongly associated with lung adenocarcinoma (OR = 8.71, p = 3 × 10^?6 and OR = 8.13, p = 0.003, respectively) and squamous-cell lung carcinoma (OR = 4.2, p = 0.001 and OR = 7.02, p = 0.002, respectively). Finally, combined susceptible genotypes of TP53 and MDM2 polymorphisms Arg72Pro and T309G were reliably associated with non-small-cell lung cancer and both its subtypes (OR = 7.9, p = 0.01; OR = 9.12, p = 0.02; OR = 7.31, p = 0.03, respectively).     

Individual and combined effects of MDM2 SNP309 and TP53 Arg72Pro on breast cancer risk: an updated meta-analysis

The tumor suppressor gene TP53 and its negative regulator murine double minute 2 are involved in multiple cellular pathways. Two potentially functional single nucleotide polymorphisms (SNPs) MDM2 SNP309 and TP53 R72P have been extensively investigated to be associated with breast cancer risk. However, the original studies as well as the subsequent meta-analysis, have yielded contradictory results for the individual effect of the two SNPs on breast cancer risk, plus that conflicting results also existed for the combined effects of MDM2 SNP309 and TP53 R72P on breast cancer risk. This meta-analysis aimed to clarify the individual and combined effects of these two genes on breast cancer risk. We performed a meta-analysis of publications with a total 9,563 cases and 9,468 controls concerning MDM2 SNP309 polymorphism and 19,748 cases and 19,962 controls concerning TP53 R72P. Odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of the association. In overall meta-analysis, individuals with the MDM2 SNP309TG genotype were associated with a borderline higher breast cancer risk than those with TT genotype (OR = 1.11, 95 % CI: 1.00-1.24, P (heterogeneity) = 0.007), whereas the TP53 R72P CC or GC genotype had no effects on breast cancer risk. In the stratified analyses, a significant association between MDM2 SNP309 and breast cancer risk were observed in Asian, but null significant association between TP53 R72P and breast cancer risk were found even in various subgroups. Moreover, no significant combined effects of MDM2 SNP309 and TP53 R72P were observed on breast cancer risk. The borderline association between MDM2 SNP309 and breast cancer risk in overall analysis should be treated with caution, and no significant combined effects for the two SNPs on breast cancer risk suggested functional investigations warranted to explore the molecular mechanism of the TP53-MDM2 circuit genes.     

Impact of TP53 Codon 72 and MDM2 SNP 309 Polymorphisms in Pancreatic Ductal Adenocarcinoma

Single-nucleotide polymorphisms (SNPs) of TP53 (codon 72, rs1042522) and MDM2 promoter (SNP 309, rs2279744) have been associated with risk for various human cancers. However, studies analyzing these polymorphisms in pancreatic ductal adenocarcinoma (PDAC) are lacking. We investigated TP53 codon 72 and MDM2 SNP 309 polymorphisms in 32 patients with PDAC, 16 patients with chronic pancreatitis (CP), and 32 normal controls, using formalin-fixed paraffin-embedded tissue. We also examined TP53 and MDM2 protein immunohistochemistry (IHC) to assess the involvement of these differences in malignant transformation and disease progression. TP53 Pro/Pro genotype was significantly more frequent in PDAC patients than in controls (65.6 vs. 15.6%, p < 0.001) and no significant difference was found between CP patients (37.5%) and controls. In MDM2 SNP 309, there were no significant differences among the three groups. Based on the Kaplan-Meier analysis, overall survival was significantly shorter in MDM2 G/G genotypes compared with other genotypes (G/T and T/T) (359 vs. 911 days, p = 0.016) whereas no significant differences in TP53 genotypes were observed (638 vs. 752 days, p = 0.471). Although TP53 IHC was frequent in PDAC patients (53.1%), TP53 and MDM2 protein expression was not correlated with polymorphisms. Our study demonstrated TP53 codon 72 polymorphism is potentially a genetic predisposing factor while MDM2 SNP 309 polymorphism might be useful in predicting survival outcome.     

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.

Methods

We 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.

Results

A 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.

Conclusions

This 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.     

Impact of TP53 codon 72 and MDM2 promoter 309 allelic dosage in a Moroccan population with hepatocellular carcinoma

Single-nucleotide polymorphisms (SNPs) in codon 72 of the TP53 gene (rs1042522) and in the promoter region of the MDM2 gene (SNP309; rs2279744) have been shown to play a role in the predisposition to many cancers. However, these findings were inconsistent in other tumor types, and ethnicity is suspected to be a critical factor influencing the effects of these SNPs on the cancer risk. The aim of the present study was to investigate whether these functional SNPs were associated with an enhanced risk of liver tumorigenesis in Moroccan patients. We have genotyped both polymorphisms in 96 patients with hepatocellular carcinoma (HCC) and 222 controls without HCC matched for age, gender and ethnicity by PCR-RFLP confirmed by sequencing. A joint effect between the MDM2 and TP53 polymorphisms and an increased risk of liver cancer was detected, with the odds ratio for the presence of both MDM2 309GG and TP53 72Pro/Pro genotypes being 10 (95% confidence interval 0.39-255.55). Interestingly, a significant increase in the HCC risk was observed when at least two deleterious alleles were present, indicating an allele dosage effect. There was no evidence for any association with early age of HCC onset when deleterious alleles of MDM2 SNP309 and TP53 Arg72Pro where present. Our findings suggest that the combination of TP53 72Pro and MDM2 309G polymorphisms enhance the risk of developing HCC. These results deserve further confirmation in other populations.     

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.     

Influence of Arg72Pro polymorphisms of TP53 on the response of buccal cells to radiotherapy

Polymorphisms in the TP53 gene codon 72 (Arg72Pro) influence apoptosis induction and DNA damage repair. We evaluated how variants of protein p53 (p53Arg and p53Pro) affect cell death and DNA damage repair by analyzing the frequencies of karyorrhexis and micronuclei. There were significant differences in the frequency of karyorrhexis between the three p53 genotypes (Arg/Arg, Arg/Pro, and Pro/Pro), between samples taken before and after radiotherapy, and between patients and controls. The frequency of micronucleated cells increased significantly after radiotherapy. There were no significant differences in the micronucleus frequency in healthy tissues of these patients compared to controls, or in the comparisons between the three genotypes. We conclude that Arg72Pro polymorphism influences cell apoptotic capacity. This is the first study investigating karyorrhexis and micronuclei, as indicators of apoptosis after radiotherapy, and how these indicators are influenced by the TP53 polymorphism Arg72Pro.     

Polymorphisms of p53 codon 72 and MDM2 promoter 309 and the risk of endometrial cancer

Genetic polymorphisms of p53 and its negative regulator murine double minute 2 homolog (MDM2) have been shown to be closely associated with tumorigenesis in a variety of human cancers. In the present study, single nucleotide polymorphism (SNP) at p53 codon 72 and MDM2 promoter 309 was examined for germline DNA samples from 102 endometrial cancer cases and 95 controls using polymerase chain reaction-based fragment analysis. There were no significant differences in the genotype and allele prevalence between control subjects and endometrial cancer patients for p53 codon 72. The GG genotype frequency of MDM2-SNP309 was statistically higher in endometrial cancer patients than that in normal healthy women when compared with the TG genotype ( P = 0.0088). However, no statistically significant differences were found between the TT and TG or GG genotype frequencies and allele prevalence. Interestingly, the combination of the homozygous Arg/Arg genotype of p53 codon 72 and homozygous GG genotype of MDM2 SNP309 polymorphisms was significantly associated with the risk of endometrial cancer (odds ratio = 3.28, 95% confidence interval = 1.13 to 9.53, P = 0.0212). The homozygous variants of wild p53 codon 72 and mutant MDM2 promoter 309 may cooperatively increase the risk of endometrial cancer in a Japanese population.     

Prognostic value of TP53 Pro47Ser and Arg72Pro single nucleotide polymorphisms and the susceptibility to gliomas in individuals from Southeast Brazil

The TP53 tumor suppressor gene codifies a protein responsible for preventing cells with genetic damage from growing and dividing by blocking cell growth or apoptosis pathways. A common single nucleotide polymorphism (SNP) in TP53 codon 72 (Arg72Pro) induces a 15-fold decrease of apoptosis-inducing ability and has been associated with susceptibility to human cancers. Recently, another TP53 SNP at codon 47 (Pro47Ser) was reported to have a low apoptosis-inducing ability; however, there are no association studies between this SNP and cancer. Aiming to study the role of TP53 Pro47Ser and Arg72Pro on glioma susceptibility and oncologic prognosis of patients, we investigated the genotype distribution of these SNPs in 94 gliomas (81 astrocytomas, 8 ependymomas and 5 oligodendrogliomas) and in 100 healthy subjects by the polymerase chain reaction-restriction fragment length polymorphism approach. Chi-square and Fisher exact test comparisons for genotype distributions and allele frequencies did not reveal any significant difference between patients and control groups. Overall and disease-free survivals were calculated by the Kaplan-Meier method, and the log-rank test was used for comparisons, but no significant statistical difference was observed between the two groups. Our data suggest that TP53 Pro47Ser and Arg72Pro SNPs are not involved either in susceptibility to developing gliomas or in patient survival, at least in the Brazilian population.     

Association of p53 Arg72Pro polymorphism with bladder cancer: A meta-analysis

Background

p53 tumor suppressor gene Arg72Pro polymorphism has been associated with bladder cancer. However, results were inconsistent. We performed this meta-analysis to estimate the association between p53 Arg72Pro polymorphism and bladder cancer.

Methods

Electronic search of PubMed was conducted to select studies. Studies containing available genotype frequencies of Arg72Pro were chosen, and pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the association.

Results

The final meta-analysis included 14 published studies with 2176 bladder cancer cases and 2798 controls. The results suggested that the variant genotype was associated with the bladder cancer risk (additive model: OR = 1.72, 95% CI: 1.036–1.325, P = 0.011; dominant model: OR = 1.268, 95% CI: 1.003–1.602, P = 0.047) in Asian subgroup. However, the association was not significant between this polymorphism and bladder cancer risk in Caucasian (additive model: OR = 0.773, 95% CI: 0.564–1.059, P = 0.109; dominant model: OR = 0.685, 95% CI: 0.418–1.124, P = 0.134).

Conclusion

This meta-analysis suggests that p53 Arg72Pro polymorphism is associated with increased risk of bladder cancer in Asians. To validate the association between this polymorphism and bladder cancer, further studies with larger participants worldwide are needed.     

Association of p53 Arg72Pro polymorphism with gastric cancer: a meta-analysis

Background: p53 tumor suppressor gene Arg72Pro polymorphism has been associated with gastric cancer. However, results were inconsistent. We performed this meta-analysis to estimate the association between p53 Arg72Pro polymorphism and gastric cancer.

Methods: An electronic search of PubMed was conducted to select studies. Studies containing available genotype frequencies of Arg72Pro were chosen, and the association was assess by pooled odds ratio (ORs) with 95% confidence interval (CIs).

Results: The meta-analysis suggested that the p53 Arg72Pro was associated with the gastric cancer risk (Additive model: OR = 1.149, 95% CI = 1.045–1.263, p = 0.004; Dominant model: OR = 1.18, 95% CI = 1.049–1.328, p = 0.006; Recessive model: OR = 1.202, 95% CI = 1.013–1.427, p = 0.035) in Asian subgroup.

Conclusion: This meta-analysis suggests that p53 Arg72Pro polymorphism is associated with increased risk of gastric cancer in Asians.     

Increased Risk of Cutaneous Melanoma Associated with p53 Arg72Pro Polymorphism

Objective

The objective of this study was to test the hypothesis that p53 Arg72Pro polymorphism may contribute to an increased risk of cutaneous melanoma (CM).

Methods

By searching the databases of PubMed, EMBASE, and Web of Science, a total of 8 eligible case-control studies with 1,957 CM cases and 2,887 controls were included in this meta-analysis. Stata software was used to analyze all the statistical data.

Results

The pooled data by a fixed-effects model suggested an increased risk of CM associated with p53 Arg72Pro polymorphism under the genetic model of Arg/Pro vs. Pro/Pro without heterogeneity (OR_{Arg/Pro vs. Pro/Pro} = 1.76, 95% CI = 1.55-1.99, P _{heterogeneity} = 0.075). A similar trend was seen in subgroups of hospital-based studies and population-based studies.

Conclusion

Our meta-analysis based on all studies shows that the p53 Arg72Pro polymorphism may increase individual susceptibility to CM, particularly in Caucasians and could serve as a biomarker to predict the population at high risk of CM.     

The T309G MDM2 Gene Polymorphism Is a Novel Risk Factor for Proliferative Vitreoretinopathy

Proliferative vitreoretinopathy (PVR) is still the major cause of failure in retinal detachment (RD) surgery. It is believed that down-regulation in the p53 pathway could be an important key in PVR pathogenesis. The purpose was to evaluate the impact of T309G MDM2 polymorphism (rs2279744) in PVR. Distribution of T309G MDM2 genotypes among European subjects undergoing RD surgery was evaluated. Proportions of genotypes between subsamples from different countries were analyzed. Also, a genetic interaction between rs2279744 in MDM2 and rs1042522 in p53 gene was analyzed. Significant differences were observed comparing MDM2 genotype frequencies at position 309 of intron 1 between cases (GG: 21.6%, TG: 54.5%, TT: 23.8%) and controls (GG: 7.3%, TG: 43.9%, TT: 48.7%). The proportions of genotypes between sub-samples from different countries showed a significant difference. Distribution of GG genotype revealed differences in Spain (35.1–53.0)/(22.6–32.9), Portugal (39.0–74.4)/(21.4–38.9), Netherlands (40.6–66.3)/(25.3–38.8) and UK (37.5–62.4)/(23.3–34.2). The OR of G carriers in the global sample was 5.9 (95% CI: 3.2 to 11.2). The OR of G carriers from Spain and Portugal was 5.4 (95% CI: 2.2–12.7), whereas in the UK and the Netherlands was 7.3 (95% CI: 2.8–19.1). Results indicate that the G allele of rs2279744 is associated with a higher risk of developing PVR in patients undergoing a RD surgery. Further studies are necessary to understand the role of this SNP in the development of PVR.     

A quadruplex tetra-primer ARMS-PCR method for the simultaneous detection of TP53 Arg72Pro, IVS3 16bp Del/Ins and IVS6+62A>G, and NQO1 C609T polymorphisms

The apoptotic pathway has been shown to be crucial in the development of cancers in addition to a variety of neurodegenerative disorders. The tumor suppressor gene (TP53) encodes p53, the central protein in the apoptotic pathway. The NAD(P)H:quinone oxidoreductase 1, which is encoded by the NQO1 gene and, plays a direct role in apoptosis in addition to its recently discovered role as a regulator for p53. Three most commonly studied polymorphisms that were shown to affect the biochemical functions of p53 protein are the exon 4 Arg72pro, Intron 3 16bp Del/Ins, and Intron 6 A>G polymorphisms. The exon 6 C609T polymorphism was shown to significantly affect NQO1 enzymatic activity. The currently used methods for the separate detection of the four polymorphisms are either slow and laborious or extremely expensive. In this paper, a new highly optimized method for the simultaneous detection of the four polymorphisms is described. The proposed method utilizes 13 primers in a single PCR reaction to detect the four polymorphisms simultaneously based on the principle of tetra-primer ARMS-PCR (also known as PCR-CTPP). The proposed method offers extremely fast, economical, and simple detection. The proposed method was successfully applied to a sample of the Syrian population (n=144), where we found a unique distribution for TP53 polymorphisms that differed from the major ethnic groups. The proposed method is the first to simultaneously detect four polymorphisms including 3 SNPs in a single PCR reaction based on tetra-primer ARMS-PCR or PCR-CTPP, and can serve as an invaluable tool for the investigation of TP53 haplotypes and the combined effects of the TP53 and NQO1 genes with respect to apoptosis and susceptibility for various types of cancers and neurodegenerative disorders.     

Haplotype analysis of p53 polymorphisms: Arg72Pro,Ins16bp and G13964C in Tunisian patients with familial or sporadic breast cancer

Background: The p53 polymorphisms have been extensively studied as putative breast cancer susceptibility variants. The present study was undertaken to investigate the association of p53 Arg72Pro, Ins16bp and G13964C polymorphisms and their haplotypes with breast cancer risk in Tunisian women. Methods: Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on 159 patients and 132 controls. Results: The G13964C intronic variant was significantly associated with familial breast cancer risk (p = 0.0018) while the genotypic distribution was similar for p53 Arg72Pro and Ins16bp in patients and controls. Moreover, the (NoIns-C), (Arg-C) and (NoIns-Arg-C) haplotypes were significantly associated with familial breast cancer risk (p = 0.0021, p = 0.0096 and p = 0.0084, respectively) while there was a trend of association between the (Ins-Arg) and (Ins-Arg-G) haplotypes and the risk of sporadic breast cancer. Only the G/C genotype as well as the (NoIns-C) haplotype remained significant after correction for multiple testing. Conclusion: Our data revealed an association between the G/C genotype and the (NoIns-C) haplotype and the risk of familial breast cancer in Tunisian women. However, these observations need to be confirmed due to the limited statistical power of our study and the small number of cases.     

Meta-analysis shows significant association of the <Emphasis Type="Italic">TP53</Emphasis> Arg72Pro with ovarian cancer risk

Growing bodies of studies have been conducted on the association of TP53 Arg72Pro polymorphism with susceptibility to ovarian cancer and have yielded conflicting results. Thus, a meta-analysis was performed to summarize the possible association. 18 case–control studies, including 2,193 ovarian cancer cases and 5,175 controls were identified. The quality of the studies was assessed according to a predefined scale. The strength of the associations between TP53 Arg72Pro polymorphism and ovarian cancer was measured by crude odds ratios (ORs) with 95% confidence intervals (CIs). Overall, no significant association was found between TP53 Arg72Pro polymorphism and ovarian cancer risk when all studies pooled into the meta-analysis in all genetic model. In the subgroup analysis by ethnicity, still no association of this polymorphism with ovarian cancer risk was obtained for all comparison models. However, significantly decreased risks of ovarian cancer were found for Arg/Arg versus Arg/Pro+Pro/Pro (OR 0.84, 95% CI 0.74–0.96) when the analysis was restricted to high quality studies. Conversely, when it was restricted to low quality studies, significantly increased risks were observed for Arg/Arg versus Pro/Pro (OR 1.58, 95% CI 1.09–2.28) and Arg/Arg+Arg/Pro versus Pro/Pro: (OR 1.50, 95% CI 1.10–2.06), which might be spurious due to the poor design of these studies. In conclusion, this meta-analysis suggests that the Arg allele is at a moderately reduced risk for ovarian cancer and this polymorphism might protect against ovarian carcinogenesis.     

MDM2 gene amplification is correlated to tumor progression but not to the presence of SNP309 or TP53 mutational status in primary colorectal cancers

Mdm2 is the main regulator of p53 and is amplified in approximately 7% of all human cancers. MDM2 gene amplification as well as expression has been correlated to an increased tumorigenic potential. We have analyzed the prevalence of MDM2 gene amplifications and SNP309 in 284 colorectal tumors using a relatively new highly sensitive PCR/ligase detection reaction method in relation to TP53 mutational status and genomic instability. We found MDM2 to be amplified in 9% of the 284 colorectal cancers analyzed and a significantly higher proportion of tumors with high MDM2 gene amplification retained a wild-type p53 gene (P = 0.058). MDM2 gene amplification was significantly correlated to advanced tumor stage. Several small-molecule MDM2 antagonists have already been identified that either physically inhibit the p53-MDM2 binding or the E3 ligase function of MDM2. Our results suggest that MDM2 is a promising target for this type of cancer therapy in a substantial subgroup of colorectal cancers.     

Association of polymorphous markers Pro72Arg and C(-594)CC OF TP53 gene with diabetic polyneuropathy in patients with type 1 diabetes mellitus living in Moscow

The aim of this study was the search of association of polymorphous markers Pro72Arg and C(-594)CC of TP53 gene with diabetic polyneuropathy (DPN) in patients with type 1 diabetes mellitus with or without clinical signs of DPN. We have found that polymorphous marker Pro72Arg of TP53 gene was associated with DPN in Russian patients with type 1 diabetes mellitus living in Moscow. The carriers of Arg allele and Arg/Arg genotype had higher risk of DPN development (OR = 1.96; CI = 1.32-2.90; and OR = 2.14; CI = 1.23-3.73; relatively). On the contrary, the carriage of Pro allele was associated with the lower risk of DPN development (OR = 0.51; CI = 0.34-0.76). We have not found any association of polymorphous marker C(-594)CC of TP53 gene with DPN in Russian patients with type 1 diabetes mellitus living in Moscow.