Is MDM2 SNP309 Variation a Risk Factor for Head and Neck Carcinoma?: An Updated Meta-Analysis Based on 11,552 Individuals.
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ABSTRACT:
SUBMITTER: Zhuo X
PROVIDER: S-EPMC4782892 | biostudies-literature | 2016 Mar
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe tumor suppressor gene p53 is involved in multiple cellular pathways including apoptosis, transcriptional control, and cell cycle regulation. In the last decade it has been demonstrated that the single nucleotide polymorphism (SNP) at codon 72 of the p53 gene is associated with the risk for development of various neoplasms. MDM2 SNP309 is a single nucleotide T to G polymorphism located in the MDM2 gene promoter. From the time that this well-characterized functional polymorphism was identified, a variety of case-control studies have been published that investigate the possible association between MDM2 SNP309 and cancer risk. However, the results of the published studies, as well as the subsequent meta-analyses, remain contradictory.MethodsTo investigate whether currently published epidemiological studies can clarify the potential interaction between MDM2 SNP309 and the functional genetic variant in p53 codon72 (Arg72Pro) and p53 mutation status, we performed a meta-analysis of the risk estimate on 27,813 cases with various tumor types and 30,295 controls.ResultsThe data we reviewed indicated that variant homozygote 309GG and heterozygote 309TG were associated with a significant increased risk of all tumor types (homozygote comparison: odds ratio (OR) = 1.25, 95% confidence interval (CI) = 1.13-1.37; heterozygote comparison: OR = 1.10, 95% CI = 1.03-1.17). We also found that the combination of GG and Pro/Pro, TG and Pro/Pro, GG and Arg/Arg significantly increased the risk of cancer (OR = 3.38, 95% CI = 1.77-6.47; OR = 1.88, 95% CI = 1.26-2.81; OR = 1.96, 95% CI = 1.01-3.78, respectively). In a stratified analysis by tumor location, we also found a significant increased risk in brain, liver, stomach and uterus cancer (OR = 1.47, 95% CI = 1.06-2.03; OR = 2.24, 95%CI = 1.57-3.18; OR = 1.54, 95%CI = 1.04-2.29; OR = 1.34, 95%CI = 1.07-1.29, respectively). However, no association was seen between MDM2 SNP309 and tumor susceptibility in the stratified analysis by p53 mutation status (GG vs TT: OR = 1.17, 95% CI = 0.75-1.82 and TG vs TT: OR = 1.09, 95% CI = 0.89-1.34 for positive p53 mutation status; GG vs TT: OR = 0.95, 95% CI = 0.72-1.25 and TG vs TT: OR = 1.06, 95% CI = 0.85-1.30 for negative p53 mutation status).ConclusionsThe analyses indicate that MDM2 SNP309 serves as a tumor susceptibility marker, and that there is an association between MDM2 SNP309 and p53 Arg72Pro regarding tumor susceptibility. Further studies that take into consideration environmental stresses and functional genetic variants in the p53-MDM2-related genes are warranted.
| S-EPMC3115916 | biostudies-literature
Project description:BackgroundThe mouse double minute 2 (MDM2) gene encodes a phosphoprotein that interacts with P53 and negatively regulates its activity. 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 colorectal cancer (CRC) risk reported conflicting results. We performed a meta-analysis of all available studies to explore the association of this polymorphism with CRC risk.MethodsAll studies published up to July 2013 on the association between MDM2 SNP309 polymorphism and CRC risk were identified by searching electronic databases PubMed, EMBASE, and Chinese Biomedical Literature database (CBM) databases. The association between the MDM2 SNP309 polymorphism and CRC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).ResultsA total of 14 case-control studies including 4460 CRC cases and 4828 controls were identified. We did not find a significant association between the MDM2 SNP309 polymorphism and CRC risk in all genetic models in overall population. However, in subgroup analysis by ethnicity, significant associations were found in Asians (TG vs. TT: OR = 1.197, 95% CI = 1.055-1.358, P=0.005; GG+TG vs. TT: OR = 1.246, 95% CI = 1.106-1.404, P=0.000) and Africans. When stratified by HWE in controls, significantly increased risk was also found among the studies consistent with HWE (TG vs. TT: OR = 1.166, 95% CI = 1.037-1.311, P= 0.010). In subgroup analysis according to p53 mutation status, and gender, no any significant association was detected.ConclusionsThe present meta-analysis suggests that the MDM2 is a candidate gene for CRC susceptibility. The MDM2 SNP309 polymorphism may be a risk factor for CRC in Asians.
| S-EPMC3786895 | biostudies-literature
Project description:Previous reports have indicated that MDM2 T309G polymorphism might be a risk factor for various cancers. Increasing studies have been conducted on the association of MDM2 T309G polymorphism with hepatocellular carcinoma (HCC) risk. However, the results remain inconclusive. Thus, the present study aimed to address this controversy by meta-analysis. Relevant literature up to Oct 2014 was searched and screened. Necessary information was rigorously extracted for data pooling and analyzing. Separate analyses on ethnicity, source of controls, sample size and P53 polymorphism status were also performed. As a result, eleven case-control studies were selected and the overall data indicated a significant association of MDM2 T309G polymorphism with HCC risk (GG vs. TT: OR=2.31; 95% CI=1.66-3.20; dominant model: OR=1.83; 95% CI=1.36-2.47; recessive model: OR=1.73; 95% CI=1.49-2.00). Similar results could be shown in the subgroups regarding ethnicity, source of controls and sample size. Interestingly, in the subgroup analysis regarding P53 codon 72 polymorphism, increased HCC risk could be observed in the Pro/Pro+Pro/Arg subgroup under a recessive model (OR=1.78; 95% CI=1.29-2.44). In conclusion, the results of the present study suggest that MDM2 T309G polymorphism might be a low-penetrant risk factor for HCC. Homozygous GG alleles might interact with Pro of P53 and thus confer the susceptibility to HCC.
| S-EPMC4483806 | biostudies-literature
Project description:Epidemiological studies have determined the associations between polymorphisms on the promoter of MDM2 (SNP309) and the codon 72 on exon 4 of p53 (p53 Arg72Pro) and the risk of hepatocellular carcinoma (HCC); however, the results were not always consistent. The aim of the present meta-analysis was to evaluate the overall associations between these 2 variants and HCC risk.The MEDLINE, Web of science, EMBASE, Cochrane Library, and CNKI databases were searched for eligibility studies and the data were synthesized under the fixed- or random-effects model. Heterogeneity among the studies was evaluated with the Cochrane test Q and I statistic.For MDM2 SNP309, the pooled odds ratio (OR) from 15 independent studies with a total of 4038 cases and 5491 controls suggested a significant association for the variant with HCC risk [allele model, G vs T: pooled OR = 1.48, 95% confidence interval (95% CI) = 1.26-1.73; pooled OR = 1.53, 95% CI = 1.26-1.81, for G/T vs T/T; pooled OR = 2.04, 95% CI = 1.54-2.71 for G/G vs T/T]. For p53 Arg72Pro, a total of 21 studies with 7285 cases and 9710 controls suggested that the variant was also associated with HCC risk under common genetic model (allele Pro vs Arg, pooled OR = 1.13, 95% CI = 1.02-1.25; Pro/Pro vs Arg/Arg, pooled OR = 1.32, 95% CI =1.06-1.64). No publication bias was found for all the meta-analysis as suggested by the Begg funnel plot and Egger tests.These results suggested that variants MDM2 SNP309 and p53 Arg72Pro are susceptibility factors for HCC; however, more studies are warranted to validate the results.
| S-EPMC6392589 | biostudies-literature
Project description:AimTo investigate the risk association and compare the onset age of hepatocellular carcinoma (HCC) patients in Taiwan with different genotypes of MDM2-SNP309.MethodsWe analyzed MDM2-SNP309 genotypes from 58 patients with HCC and 138 cancer-free healthy controls consecutively. Genotyping of MDM2-SNP309 was conducted by restriction fragment length polymorphism assay.ResultsThe proportion of homozygous MDM2-SNP309 genotype (G/G) in cases and cancer-free healthy controls was similar (17.2% vs 16.7%). Multivariate analysis showed that the risk of G/G genotype of MDM2-SNP309 vs wild-type T/T genotype in patients with HCC was not significant (OR = 1.265, 95% CI = 0.074-21.77) after adjustment for sex, hepatitis B or C virus infection, age, and cardiovascular disease/diabetes. Nevertheless, there was a trend that GG genotype of MDM2-SNP309 might increase the risk in HCC patients infected with hepatitis virus (OR = 2.568, 95% CI = 0.054-121.69). Besides, the homozygous MDM2-SNP309 genotype did not exhibit a significantly earlier age of onset for HCC.ConclusionCurrent data suggest that the association between MDM2-SNP309 GG genotype and HCC is not significant, while the risk may be enhanced in patients infected by hepatitis virus in Taiwan.
| S-EPMC2785064 | biostudies-literature
Project description:BackgroundMDM2 is a major negative regulator of p53, and a single nucleotide polymorphism (SNP) in the MDM2 promoter region SNP309 has been demonstrated to be associated with an increased MDM2 expression and a significantly earlier age of onset of several tumors, including gastric cancer. Several studies were published to evaluate the association between SNP309 and gastric cancer risk. However, the results remain conflicting rather than conclusive.ObjectiveThe aim of this study was to assess the association between the MDM2 SNP309 polymorphism and gastric risk.MethodsWe performed a meta-analysis to investigate this relationship. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively.ResultsFive published case-control studies, including 1,621 gastric cancer cases and 2,639 controls were identified. We found that the MDM2 SNP309 polymorphism was associated with a significantly increased risk of gastric cancer risk when all studies were pooled into the meta-analysis (GG versus TT, OR = 1.54; 95%CI = 1.04-2.29, and GG versus GT/TT, OR = 1.49, 95%CI = 1.30-1.72). Furthermore, Egger's test did not show any evidence of publication bias (P = 0.799 for GG versus TT).ConclusionOur results suggest that the MDM2 SNP309 polymorphism may be a low-penetrant risk factor for the development of gastric cancer.
| S-EPMC3581579 | biostudies-literature
Project description:BackgroundUrinary bladder carcinoma stage T1 is an unpredictable disease that in some cases has a good prognosis with only local or no recurrence, but in others can appear as a more aggressive tumor with progression to more advanced stages. The aim here was to investigate stage T1 tumors regarding MDM2 promoter SNP309 polymorphism, mutations in the p53 gene, and expression of p53 and p16 measured by immunohistochemistry, and subsequently relate these changes to tumor recurrence and progression. We examined a cohort of patients with primary stage T1 urothelial carcinoma of the bladder and their tumors.MethodsAfter re-evaluation of the original slides and exclusions, the study population comprised 141 patients, all with primary stage T1 urothelial carcinoma of the bladder. The hospital records were screened for clinical parameters and information concerning presence of histologically proven recurrence and progression. The paraffin-embedded tumor material was evaluated by immunohistochemistry. Any mutations found in the p53 gene were studied by single-strand conformation analysis and Sanger sequencing. The MDM2 SNP309 polymorphism was investigated by pyrosequencing. Multivariate analyses concerning association with prognosis were performed, and Kaplan-Meier analysis was conducted for a combination of changes and time to progression.ResultsOf the 141 patients, 82 had at least one MDM2 SNP309 G allele, and 53 had a mutation in the p53 gene, but neither of those anomalies was associated with a worse prognosis. A mutation in the p53 gene was associated with immunohistochemically visualized p53 protein expression at a cut-off value of 50%. In the group with p53 mutation Kaplan-Meier analysis showed higher rate of progression and shorter time to progression in patients with immunohistochemically abnormal p16 expression compared to them with normal p16 expression (p = 0.038).ConclusionsMDM2 SNP309 promoter polymorphism and mutations in p53 were not associated with worse prognosis in this cohort of patients with primary stage T1 urinary bladder carcinoma. However, patients with abnormal p16 expression and a mutated p53 gene had a higher rate of and a shorter time to progression, and p53 gene mutation was associated with an abnormal immunohistochemistry for p53 at a cut-off of 50%.
| S-EPMC3574032 | biostudies-literature
Project description:ObjectiveThe 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.MethodsAll 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).ResultsEight 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.ConclusionsThis 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.
| S-EPMC4029393 | biostudies-literature
Project description:BACKGROUND:Murine double minute 2 homolog (MDM2) plays an important role in the downregulation of P53 tumor suppressor gene. MDM2 inhibits P53 transcriptional activity and thereby results in accelerated tumor formation. Overexpression of MDM2 has been found in several cancer types including endometrial cancer. SNP309 is located in the promoter region of MDM2 and contributes to the overexpression of MDM2. The association between MDM2 SNP309 polymorphism and endometrial cancer risk has been investigated in several studies; however, the conclusion remains controversial. OBJECTIVES:We performed the present meta-analysis to give a comprehensive conclusion of the association between MDM2 SNP309 polymorphism and endometrial cancer susceptibility. METHODS:We conducted a literature research on PubMed, Embase, Cochrane Library, OVID, Web of Science, Wan Fang, CNKI, and CQVIP databases up to July 31, 2018. Newcastle-Ottawa scale was used to assess the quality of studies. We evaluated the strength of association by combining odds ratios (ORs) and 95% confidence intervals (CIs) in 5 different genetic models under a fixed-effect model or random-effect model. We further conducted subgroup analysis by ethnicity, source of control, histological type, clinical type, grade, and stage of tumor. Sensitivity analysis and publication bias were also performed. RESULTS:Nine eligible studies were finally included in our meta-analysis. We found MDM2 SNP309 polymorphism increased the risk of endometrial cancer under allele model (OR: 1.23, 95% CI: 1.06-1.41, P?=?.005), homozygote model (OR: 1.43, 95% CI: 1.13-1.81, P?=?.003) and recessive model (OR: 1.55, 95% CI: 1.17-2.04, P?=?.002). Subgroup analysis suggested a similar elevated risk in both Asians and Caucasians. We identified a strong association of enhanced susceptibility to endometrial cancer in endometrioid group (OR: 2.13, 95% CI: 1.28-3.54, P?=?.004) and Type I group (OR: 1.89, 95% CI: 1.25-2.86, P?=?.002) under dominant model. We identified no significant publication bias according to Egger's test. CONCLUSIONS:Our meta-analysis suggested that MDM2 SNP309 polymorphism increased the risk of endometrial cancer significantly, especially in endometrioid and Type I endometrial cancer, indicating MDM2 could serve as a potential diagnostic factor marker for endometrial cancer.
| S-EPMC6310604 | biostudies-other
Project description:OBJECTIVE:Human murine double minute 2 protein (MDM2) is mainly a negative regulator of p53 tumor suppressor pathway. We aimed to investigate the association between MDM2 SNP309 polymorphism and bladder cancer risk. METHODS:A total of 535 bladder cancer patients and 649 health controls were recruited for our study. MDM2 SNP309 T>G polymorphism was genotyped by polymerase chain reaction-ligase detection reaction method. Logistic regression was used to analyze the relationship between the genotype and susceptibility of bladder cancer. Kaplan-Meier estimates and log-rank test were obtained to analyze the association between the genotype and risk of recrudesce in nonmuscle-invasive bladder cancer patients. A multivariable Cox proportional hazards model was fitted to identify independent prognostic factors. To further investigate the association, we conducted a meta-analysis including six studies. RESULTS:The frequency of the MDM2 SNP309 T>G polymorphism showed no significant difference between cases and controls (all P>0.05). In the stratification analysis, the results showed that G allele carriers were prone to have a significant decrease in risk of low-grade bladder cancer (adjusted odds ratio: 0.613, 95% confidence interval: 0.427-0.881), and G variant was associated with a significantly reduced risk of recurrence in nonmuscle-invasive bladder cancer patients with or without chemotherapy (P<0.05). The results of the meta-analysis showed that G allele and GG genotype of MDM2 SNP309 polymorphism were significantly associated with increased risk of bladder cancer in Caucasians (both P<0.05), and no association was observed in total populations and Asians (P>0.05). CONCLUSION:MDM2 SNP309 T>G polymorphism has no influence on bladder cancer risk in Asians, but this single nucleotide polymorphism may be associated with genetic susceptibility of bladder cancer among Caucasians.
| S-EPMC4676618 | biostudies-literature