The MDM2 promoter SNP285C/309G haplotype diminishes Sp1 transcription factor binding and reduces risk for breast and ovarian cancer in Caucasians

MDM2 plays a key role in modulating p53 function. The MDM2 SNP309T > G promoter polymorphism enhances Sp1 binding and has been linked to cancer risk and young age at diagnosis although with conflicting evidence. We report a second MDM2 promoter polymorphism, SNP285G > C, residing on the SNP309G allele. SNP285C occurs in Caucasians only, where 7.7% (95% CI 7.6%-7.8%) of healthy individuals carry the SNP285C/309G haplotype. In?vitro analyses reveals that SNP309G enhances but SNP285C strongly reduces Sp1 promoter binding. Comparing MDM2 promoter status among different cohorts of ovarian (n?= 1993) and breast (n?= 1973) cancer patients versus healthy controls (n?= 3646), SNP285C reduced the risk of both ovarian (OR 0.74; CI 0.58-0.94) and breast cancer (OR 0.79; CI 0.62-1.00) among SNP309G carriers.     

The MDM2 285G–309G haplotype is associated with an earlier age of tumour onset in patients with Li-Fraumeni syndrome

In the Li-Fraumeni syndrome (LFS) resulting from germline TP53 mutations, the MDM2 SNP309G allele has been shown to be associated with an earlier age of tumour onset, however the significance of this association is controversial. The 285C variation, also located in the MDM2 promoter, has been shown to reduce the strength of Sp1 binding to MDM2 promoter, antagonizing the effect of the 309G variation. In this study, we investigated the interaction of the MDM2 SNP285 and 309 in a large series of 195 LFS patients. Although we observed a lower mean age of tumour onset in patients with MDM2 SNP309 T/G or G/G genotype (23.1 years) than in patients with T/T genotype (27.3 years), the difference was not statistically significant. In contrast, patients with the 285–309 G–G haplotype develop tumours 5 years earlier than patients harbouring other haplotypes (p = 0.044). This result shows that the MDM2 285–309 G–G is a higher risk haplotype in patients with germline TP53 mutations. This study confirms that the MDM2 309G variation is deleterious when its effect is not neutralized by the 285C variation and illustrates the interfering effects of SNPs located within a gene acting as modifier factor in a Mendelian disease.     

Polymorphisms in the MDM2 gene and risk of malignant bone tumors: a meta-analysis

There are several studies published to assess the associations of murine double minute 2 (MDM2) genetic polymorphisms with risk of malignant bone tumors, but they reported contradictory results and failed to confirm a strong and consistent association. To assess the evidence regarding the associations of MDM2 genetic polymorphisms with the risk of malignant bone tumors, we conducted a meta-analysis of epidemiological studies. The pooled odds ratio (OR) with its 95 % confidence intervals (95 % CI) was used to assess these possible associations. Four studies with a total of 3,958 individuals were finally included the meta-analysis. Meta-analysis of two studies on MDM2 SNP309 polymorphism showed that MDM2 SNP309 polymorphism was associated with an increased risk of malignant bone tumors (G versus T: OR?=?1.72, 95 % CI 1.35–2.20, P?<?0.001; GG versus TT: OR?=?2.64, 95 % CI 1.59–4.39, P?<?0.001; GG/GT versus TT: OR?=?1.87, 95 % CI 1.33–2.62, P?<?0.001; GG versus TT/GT: OR?=?2.20, 95 % CI 1.38–3.51, P?=?0.001). Meta-analysis of those two studies on MDM2 rs1690916 polymorphism showed that MDM2 rs1690916 minor allele A was associated with decreased risk of malignant bone tumors (OR?=?0.60, 95 % CI 0.46–0.77, P?<?0.001). Meta-analyses of available data show that there are significant associations of MDM2 SNP309 polymorphism and MDM2 rs1690916 polymorphism with malignant bone tumors.     

Current evidence on the relationship between SNP309 polymorphism in the MDM2 gene and colorectal cancer risk

It has been demonstrated that MDM2 is a well-established negative regulator of the p53 protein and might be associated with a significantly earlier age of onset of several tumors, including colorectal cancer (CRC). In recent years, a T to G substitution (SNP309) in the promoter of MDM2 has been extensively studied as a potential CRC risk factor; however, the results are inconsistent. To derive a more precise estimation of association between MDM2 SNP309 polymorphism and CRC risk, we conducted a meta-analysis of 11 studies with 4,050 CRC cases and 3,688 controls. For MDM2 SNP309 polymorphism, no obvious associations were found for all genetic models when all studies were pooled into the meta-analysis. In the subgroup analyses by ethnicity, source of controls, and Hardy–Weinberg equilibrium (HWE) in controls, a significantly increased risk was observed among Asians (heterozygous model: odds ratio (OR)?=?1.21, 95 % confidence interval (CI)?=?1.06–1.39, P?=?0.005), population-based studies (heterozygous model: OR?=?1.17, 95 % CI?=?1.02–1.34, P?=?0.027), and among studies without the HWE (recessive model: OR?=?1.42, 95 % CI?=?1.03–1.94, P?=?0.030). When excluding three studies deviated from HWE, the significant results were also observed for heterozygous model in overall population (OR?=?1.16, 95 % CI?=?1.02–1.31, P?=?0.020). No publication bias was found in the present study. In conclusion, this meta-analysis suggests that MDM2 SNP309 polymorphism was associated with CRC susceptibility, especially among Asians. Further research is needed to assess possible gene–gene or gene–environment–lifestyle interactions on CRC.     

MDM2 SNP309T>G polymorphism and hepatocellular carcinoma risk: a meta-analysis

Case–control studies on the association between mouse double-minute 2 homolog (MDM2) SNP309T>G polymorphism and hepatocellular carcinoma have provided either controversial or inconclusive results. To clarify the effect of MDM2 SNP309T>G polymorphism on the risk of hepatocellular carcinoma, a meta-analysis of all case–control observational studies was performed. Pooled odds ratios (ORs) for various polymorphisms were estimated using random and fixed effects models. The Q-statistic was used to evaluate the homogeneity, and Egger and Begg tests were used to assess publication bias. Overall, the MDM2 SNP309T>G polymorphism was associated with a risk of hepatocellular carcinoma (OR?=?0.68; 95 % CI?=?0.54–0.85 for allele contrast, p?=?0.0005, p _het?=?0.004). The contrast of homozygotes and the recessive and dominant models produced the same pattern of results as the allele contrast. In the analysis stratified by ethnicity, significant associations were found in the Caucasian population in all of the genetic models. In addition, heterogeneity disappeared in subgroups of Caucasian subjects. Our pooled data suggest evidence for a major role of MDM2 SNP309T>G polymorphism in the carcinogenesis of hepatocellular carcinoma, especially among Caucasian populations.     

Common variant on MDM2 contributes to endometrial cancer susceptibility: evidence based on 7 studies

Due to its important biological function as a key negative regulator of p53, the mouse double minute 2 homologue (MDM2) gene has been extensively studied. A functional variant in the MDM2 gene promoter, single-nucleotide polymorphism 309 (SNP309) T > G (rs2279744), has been reported to cause an increase in MDM2 protein levels and impairment of p53 tumor suppressor activity, which may be associated with the development of cancer. A number of studies were performed to investigate the relationship between this SNP and endometrial cancer. But, the results remain controversial. Thus, we performed a comprehensive meta-analysis to derive a more precise estimation of this susceptibility. There were seven eligible articles with a total of 1,278 patients and 2,189 controls included in the meta-analysis. In the present study, we found significant associations under the allele contrast and recessive model. The G allele was associated with elevated risk for endometrial cancer [allele contrast OR?=?1.33, 95 % confidence interval (CI)?=?1.12–1.58, P(Z)?=?0.0009, P(Q)?=?0.02)], while the homozygous GG genotype may also increase the risk of endometrial cancer [OR?=?1.88, 95 % CI?=?1.40–2.52, P(Z)?P(Q)?=?0.02]. In the subgroup analysis by ethnicity, we found similar significant results for both Caucasians [allele contrast OR?=?1.41, 95 % CI?=?1.04–1.92, P(Z)?=?0.03, P(Q)?=?0.001; recessive model OR?=?1.89, 95 % CI?=?1.10–3.23, P(Z)?=?0.02, P(Q)?=?0.002] and Asians [allele contrast OR?=?1.24, 95 % CI?=?1.01–1.53, P(Z)?=?0.04, P(Q)?=?0.86; recessive model OR?=?1.75, 95 % CI?=?1.24–2.45, P(Z)?=?0.001, P(Q)?=?0.75]. Overall, the meta-analysis demonstrated that the MDM2 SNP309 polymorphism may be associated with increased risk of endometrial cancer.     

MDM2 SNP309 polymorphism contributes to endometrial cancer susceptibility: evidence from a meta-analysis

Objective

The SNP309 polymorphism (T-G) in the promoter of MDM2 gene has been reported to be associated with enhanced MDM2 expression and tumor development. Studies investigating the association between MDM2 SNP309 polymorphism and endometrial cancer risk reported conflicting results. We performed a meta-analysis of all available studies to explore this association.

Methods

All studies published up to August 2013 on the association between MDM2 SNP309 polymorphism and endometrial cancer risk were identified by searching electronic databases PubMed, Web of Science, EMBASE, and Chinese Biomedical Literature database (CBM). The association between the MDM2 SNP309 polymorphism and endometrial cancer risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).

Results

Eight case–control studies with 2069 endometrial cancer cases and 4546 controls were identified. Overall, significant increase of endometrial cancer risk was found when all studies were pooled in the meta-analysis (GG vs. TT: OR = 1.464, 95% CI 1.246–1.721, P < 0.001; GG vs. TG + TT: OR = 1.726, 95% CI 1.251–2.380, P = 0.001; GG + TG vs. TT: OR = 1.169, 95% CI 1.048–1.304, P = 0.005). In subgroup analysis by ethnicity and HWE in controls, significant increase of endometrial cancer risks were observed in Caucasians and studies consistent with HWE. In subgroup analysis according to study quality, significant associations were observed in both high quality studies and low quality studies.

Conclusions

This meta-analysis suggests that MDM2 SNP309 polymorphism contributes to endometrial cancer susceptibility, especially in Caucasian populations. Further large and well-designed studies are needed to confirm this association.     

Association between MDM2 promoter SNP309 T/G polymorphism and liver cancer risk - a meta-analysis

Background: Many studies have investigated the association between the MDM2 promoter SNP309 T/Gpolymorphism and liver cancer risk, but inconsistencies make drawwing definitive conclusions difficult. Methods:We therefore searched main databases for articles relating MDM2 SNP309 T/G polymorphism to risk of livercancer in humans and estimated summary odds ratio (OR) with 95% confidence intervals (95% CI) to assessthe possible association in a meta-analysis. Results: The main analysis revealed no significant heterogeneity, andthe pooled ORs of fixed-effects were all significant (for G versus T, OR = 1.59, 95% CI 1.42-1.78; for GG versusTT, OR = 2.45, 95% CI 1.93-3.12; for GT versus TT, OR = 1.70, 95% CI 1.38-2.09; for GG versus GT, OR =1.49, 95% CI 1.24-1.79; for GG and GT versus TT, OR = 1.95, 95% CI 1.61-2.38; for GG versus TT and GT,OR = 1.73, 95% CI 1.46-2.07). Subgroup analyses by ethnicity and sensitivity analyses both showed associationsto remain significant. Conclusion: The present meta-analysis of available data showed a significant associationbetween the MDM2 SNP309 T/G polymorphism and liver cancer risk, the MDM2 SNP309 G allele contributingto increased risk in both Asians and Caucasians in a graded, dose-dependent fashion.     

MDM2 SNP309 is an ethnicity-dependent risk factor for digestive tract cancers

Published data on the relationship between T309G polymorphism in the murine double minute 2 (MDM2) gene and susceptibility of digestive tract cancers (DTC) are inconclusive. Thus, the aim of this study is to determine whether MDM2 T309G polymorphism is associated with the risk of diverse DTC, including esophagus, stomach, liver, bile duct, pancreas, and colorectum cancers. Relevant studies were identified up to October 1, 2013. Crude odds ratio (OR) and 95 % confidence interval (CI) were used as a measure of the strength of the association. The pooled result based on all studies showed that there was a statistically significant link between MDM2 T309G polymorphism and DTC susceptibility (T vs. G: OR?=?0.82, 95%CI?=?0.76–0.88). When stratified by race, significant associations were observed for all genetic models among Asians (especially in Chinese population), but not among Caucasians. Subgroup analyses according to tumor location indicated that the genetic variant was associated with esophageal (OR?=?0.88, 95%CI?=?0.81–0.96 for T vs. G), hepatocellular (OR?=?0.69, 95%CI?=?0.57–0.84 for T vs. G) and pancreatic cancer risk but not associated with cholangiocarcinoma or colorectum cancer susceptibility. Meanwhile, the G allele was also suggested to be associated with increased gastric cancer risk (OR?=?0.68, 95%CI?=?0.54–0.87 for TT?+?TG vs. GG for intestinal type of gastric cancer and OR?=?0.18, 95%CI?=?0.06–0.50 for TT vs. GG for Helicobacter pylori infection positive stomach cancer). Our study indicates that the MDM2 T309G polymorphism may be an ethnicity-dependent risk factor for DTC, especially for the upper gastrointestinal tract malignancies.     

MDM2 启动子区309 位点基因多态性与乳腺癌风险的关系*

目的:采用病例- 对照研究检测MDM2 启动子区309 位点T>G 单核苷酸多态（SNP 309）在中国女性人群中的频率分布,分析其与中国女性乳腺癌发病风险的关系。方法:提取病例组698 例原发性乳腺癌患者及对照组525 例健康人的外周血单核细胞DNA,采用聚合酶链反应- 限制性片段长度多态性（PCR-RFLP ）分析法,检测MDM2 启动子区309 位点基因多态性,确定此位点三种基因型,即T/T、T/G、G/G 基因型。统计分析病例组和对照组人群MDM2 SNP 309 各基因型频率分布,及各基因型与乳腺癌发病风险的相关性。结果:在研究的病例组与对照组整体人群中,经年龄、月经状态、家族史及生育史等因素校正后,与MDM2 SNP 309 T/T基因型比较,T/G 型及G/G 型与乳腺癌的发病风险无显著相关性（T/G,adjusted OR= 1.2,95%CI:0.8～1.6,P=0.30;G/G,adjusted OR= 1.0,95%CI:0.7～1.5,P=0.88）。 进一步分层分析后显示:在绝经后人群中,与T/T基因型比较,T/G 基因型及G/G 基因型显著增加乳腺癌的发病风险（T/G,adjusted OR= 1.8,95%CI:1.2～3.0,P=0.011;G/G,adjusted OR= 1.9,95%CI:1.2～3.3,P=0.014）。 提示绝经后人群携带T/G 型、G/G 型者比携带T/T基因型者患乳腺癌的风险分别升高约1.8、1.9 倍。在绝经前人群中,各基因型与乳腺癌的发病风险无显著相关性（P>0.05）。 结论:MDM2 启动子309 位点突变型G 等位基因携带者显著增加绝经后女性乳腺癌的发病风险。      

The MDM2 SNP309T>G Polymorphism Increases Bladder Cancer Risk among Caucasians: a Meta-analysis

Published studies have evaluated associations between the MDM2 SNP309T>G polymorphism and bladder cancer susceptibility. However, these generated inconsistent results. The aim of the present investigation was to quantify the strength of association between MDM2 SNP309T>G polymorphism and bladder cancer risk by conducting a meta-analysis. We searched PubMed and Embase for related studies that had been published in English before April 1, 2014 and associations were assessed by summarizing the odds ratios (ORs) with thecorresponding 95% confidence intervals (CIs). Five case-control studies with a total of 972 cases and 1,012 controls were finally identified to be eligible for the meta-analysis. Overall, the results indicated that there was no significant association between the MDM2 SNP309T>G polymorphism and bladder cancer risk (for the allele model G vs. T: OR=1.08, 95% CI 0.85-1.36, p=0.54; for the co-dominant model GG vs. TT: OR=1.20, 95% CI 0.74-1.93, p=0.46; for the dominant model GG+GT vs. TT: OR=0.98, 95% CI 0.80-1.20, p=0.83; for the recessive model GG vs. GT+TT: OR=1.20, 95% CI 0.83-1.74, p=0.33). However, on subgroup analysis by ethnicity, significant associations were found in Caucasians in three models (for the allele model G vs. T: OR=1.41, 95% CI 1.10-1.81, p=0.006; for the co-dominant model GG vs. TT: OR=2.16, 95% CI 1.28-3.63, p=0.004; for therecessive model GG vs. GT+TT: OR=2.06, 95% CI 1.31-3.22, p=0.002). In summary, the present meta-analysis provides evidence that the genotype for the MDM2 SNP309T>G polymorphism may be associated with genetic susceptibility to bladder cancer among Caucasians.     

High-risk HPV infection after five years in a population-based cohort of Chilean women

Background

Single-nucleotide polymorphisms within TP53 gene (codon 72 exon 4, rs1042522, encoding either arginine or proline) and MDM2 promoter (SNP309; rs2279744), have been independently associated with increased risk of several cancer types. Few studies have analysed the role of these polymorphisms in the development of hepatocellular carcinoma.

Methods

Genotype distribution of TP53 codon 72 and MDM2 SNP309 in 61 viral hepatitis-related hepatocellular carcinoma cases and 122 blood samples (healthy controls) from Italian subjects were determined by PCR and restriction fragment length polymorphism (RFLP).

Results

Frequencies of TP53 codon 72 alleles were not significantly different between cases and controls. A significant increase of MDM2 SNP309 G/G and T/G genotypes were observed among hepatocellular carcinoma cases (Odds Ratio, OR = 3.56, 95% Confidence Limits, 95% CI = 1.3-9.7; and OR = 2.82, 95% CI = 1.3-6.4, respectively).

Conclusions

These results highlight a significant role of MDM2 SNP309 G allele as a susceptibility gene for the development of viral hepatitis-related hepatocellular carcinoma among Italian subjects.     

No association of the MDM2 SNP309 polymorphism with risk of breast or ovarian cancer

A functional T to G germline polymorphism in the promoter region of MDM2 (SNP309) has been reported to profoundly accelerate tumor formation suggesting that it may also represent a powerful cancer predisposing allele. To investigate the role of SNP309 in cancer predisposition we undertook a case-control study of this polymorphism among 351 women diagnosed with breast cancer, 302 women diagnosed with ovarian and 258 female controls from a British population. The GG genotype was not associated with either breast cancer (OR 1.04, 95% CI 0.67–1.60) or ovarian cancer (OR 0.86, 95% CI 0.53–1.37). This study has found no evidence that the GG genotype of the MDM2 SNP309 polymorphism is associated with early onset or familial breast cancer or with ovarian cancer.     

MDM2 SNP309 variation increases cervical cancer risk among Asians

MDM2 T309G polymorphism has been suggested to be a risk factor for a number of cancers. The association of MDM2 T309G genetic variation with cervical cancer risk remains inconclusive. In the present study, we aimed to get a more confidential result by conducting a quantitative meta-analysis. Relevant literature up to October 2013 was searched and screened. Essential information was rigorously extracted for data pooling and analyzing, and then, separate analyses on ethnicity and source of controls were also performed. As a result, four articles including five case–control studies were selected. The overall data failed to show a significant association between MDM2 T309G polymorphism and cervical cancer risk (GG vs TT: odds ratio (OR)?=?1.31; 95 % confidence interval (CI)?=?0.55–3.13; dominant model: OR?=?1.22; 95 % CI?=?0.65–2.31; recessive model: OR?=?1.45; 95 % CI?=?0.79–2.65). However, in the subgroup analysis about ethnicity, increased cancer risk could be shown among Asians (GG vs TT: OR?=?2.15; 95 % CI?=?1.03–4.51; recessive model: OR?=?2.01; 95 % CI?=?1.32–3.06). In conclusion, the results of the present study suggest that homozygous GG alleles of MDM2 T309G polymorphism might be a risk factor for cervical cancer among Asians. Further studies are needed get a more definitive conclusion.     

Polymorphisms at p53, p73, and MDM2 loci modulate the risk of tobacco associated leukoplakia and oral cancer

Polymorphisms at loci controlling cellular processes such as cell cycle, DNA repair, and apoptosis may modulate the risk of cancer. We examined the association of two linked polymorphisms (G4C14–A4T14) at p73 and one polymorphism (309G > T) at MDM2 promoter with the risk of leukoplakia and oral cancer. The p73 and MDM2 genotypes were determined in 197 leukoplakia patients, 310 oral cancer patients and in 348 healthy control subjects. The p73 GC/AT genotype increased the risk of leukoplakia (OR = 1.6, 95% CI = 1.1–2.3) and oral cancer (OR = 2.4, 95% CI = 1.7–3.3) but the 309G > T MDM2 polymorphism independently could not modify the risk of any of the diseases. Stratification of the study population into subgroups with different tobacco habits showed that the risk of the oral cancer is not modified further for the individuals carrying p73 risk genotype. However, leukoplakia patients with smokeless tobacco habit showed increased risk with combined GC/AT and AT/AT (OR = 3.0, 95% CI = 1.3–7.0) genotypes. A combined analysis was done with our previous published data on p53 codon 72 pro/arg polymorphism. Analysis of pair wise genotype combinations revealed increase in risk for specific p73‐MDM2 and p73‐p53 genotype combinations. Finally, the combined three loci analyses revealed that the presence of at least one risk allele at all three loci increases the risk of both leukoplakia and oral cancer. © 2009 Wiley‐Liss, Inc.