The MDM2 309T>G Polymorphism and Ovarian Cancer Risk: A Meta-Analysis of 1534 Cases and 2211 Controls

Background

Recently, there have been a number of studies on the association between MDM2 (Murine Double Minute 2) 309 polymorphism and ovarian cancer risk. However, the results of previous reports remain controversial and ambiguous. Thus, we performed a meta-analysis to explore more precisely the association between MDM2 309 polymorphism and the risk of ovarian cancer.

Methods

A meta-analysis was performed to examine the association between MDM2 309T>G polymorphism and ovarian cancer risk. Odds ratio (OR) and its 95% confidence interval (CI) were used for statistical analysis.

Results

Our publication search identified a total of 6 studies with 1534 cases and 2211 controls. No significant association was found between MDM2 309T>G polymorphism and ovarian cancer risk in total population analysis. In the subgroup meta-analysis by ethnicity, a negative association was shown in Asian subgroup (G vs. T OR = 0.774, 95% CI = 0.628–0.955, P = 0.017, P _het = 0.327; GG vs. TT: OR = 0.601, 95% CI = 0.395–0.914, P = 0.017, P _het = 0.417; dominant model TG+GG vs. TT: OR = 0.661, 95% CI = 0.468–0.934, P = 0.019, P _het = 0.880), and no significant association in any genetic models among Caucasians was observed.

Conclusions

This meta-analysis provides evidence for the association between MDM2 309 polymorphism and ovarian cancer risk, supporting the hypothesis that MDM2 SNP309 G allele acts as an important ovarian cancer protective factor in Asians but not in Caucasians.     

MDM2 SNP309 rs2279744 Polymorphism and Gastric Cancer Risk: A Meta-Analysis

Background

MDM2 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.

Objective

The aim of this study was to assess the association between the MDM2 SNP309 polymorphism and gastric risk.

Methods

We 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.

Results

Five 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).

Conclusion

Our results suggest that the MDM2 SNP309 polymorphism may be a low-penetrant risk factor for the development of gastric cancer.     

Association of microRNA-499 rs3746444 Polymorphism with Cancer Risk: Evidence from 7188 Cases and 8548 Controls

Background

Owing to inconsistent and inconclusive results, we performed a meta-analysis to derive a more precise estimation of the association between miR-499 rs3746444 polymorphism and cancer risk.

Methodology/Principal Findings

A systematic search of the Pubmed, Excerpta Medica Database (Embase) and Chinese Biomedical Literature Database (CBM) databases was performed with the last search updated on May 6, 2012. The odds ratio (OR) and its 95% confidence interval (95%CI) were used to assess the strength of the association. A total of 15 independent studies including 7,188 cases and 8,548 controls were used in the meta-analysis. In the present meta-analysis, we found a significant association between miR-499 rs3746444 polymorphism and cancer risk in the overall analysis (G versus A: OR = 1.10, 95%CI 1.01–1.19, P = 0.03; GG+AG versus AA: OR = 1.15, 95%CI 1.02–1.30, P = 0.02; GG versus AG+AA: OR = 1.07, 95%CI 0.89–1.28, P = 0.50; GG versus AA: OR = 1.13, 95%CI 0.98–1.31, P = 0.09; AG versus AA: OR = 1.16, 95%CI 1.02–1.33, P = 0.03). In the subgroup analysis by ethnicity, miR-499 rs3746444 polymorphism was significantly associated with cancer risk in Asian population. In the subgroup analysis by cancer types, miR-499 rs3746444 polymorphism was significantly associated with breast cancer.

Conclusions/Significance

This meta-analysis suggests a significant association between miR-499 rs3746444 polymorphism and cancer risk. Large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis.     

MDM2 SNP309 contributes to tumor susceptibility: a meta-analysis

The potentially functional polymorphism,SNP309,in the promoter region of MDM2 gene has been implicated in cancer risk,but individual published studies showed inconclusive results.To obtain a more precise estimate of the association between MDM2 SNP309 and risk of cancer,we performed a meta-analysis of 70 individual studies in 59 publications that included 26,160 cases with different types of tumors and 33,046 controls.Summary odds ratios (OR) and corresponding 95％ confidence intervals (CIs) were estimated using fixed- and random-effects models when appropriate.Overall,the variant genotypes were associated with a significantly increased cancer risk for all cancer types in different genetic models (GG vs.TT:OR,1.123; 95％ CI,1.056-1.193; GG/GT vs.TT:OR,1.028; 95％ CI,1.006-1.050).In the stratified analyses,the increased risk remained for the studies of most types of cancers,Asian populations,and hospital-/population-based studies in different genetic models,whereas significantly decreased risk was found in prostate cancer (GG vs.TT:OR,0.606; 95％ CI,0.407-0.903; GG/GT vs.TT:OR,0.748; 95％ CI,0.579-0.968).In conclusion,the data of meta-analysis suggests that MDM2 SNP309 is a potential biomarker for cancer risk.     

MDM2 SNP309 polymorphism and breast cancer risk: a meta-analysis

The mouse double minute 2 (MDM2) gene encodes a phosphoprotein that interacts with P53 and negatively regulates its activity. SNP309 polymorphism (T-G) in the promoter of MDM2 gene has been reported to be associated with enhanced MDM2 expression and tumor development. Many published studies have evaluated the association between MDM2 SNP309 polymorphism and breast cancer risk. However, the results were inconsistent. We combined and analyzed the data from 19 case–control studies including 14,450 cases and 13,382 controls. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association between MDM2 SNP309 polymorphism and breast cancer risk. No significant association was found in all genetic models in overall population. However, in subgroup analysis by ethnicity (4 studies in Asian group, 13 studies in European group, 2 studies of mixed population which were separated into 2 European population group and 2 African population group), we found an increased breast cancer susceptibility for GT versus TT (OR = 1.31, 95% CI = 1.03–1.67) in Asian population and for GT versus TT (OR = 1.31, 95% CI = 1.03–1.66) in African population. When stratified by family history status (5 studies in familial breast cancer group, 5 studies in sporadic breast cancer group), homozygous subjects of sporadic breast cases carrying the T309G G allele exhibited elevated breast cancer risk (OR = 1.35, 95% CI = 1.00–1.82), whereas heterozygous carriers did not show significant association with breast cancer risk for GT vs. TT (OR = 1.26, 95% CI = 0.84–1.87). Our meta–analysis suggests that MDM2 SNP309 polymorphism may increase the risk to breast cancer in Asian and African population.     

MDM2 SNP309 is associated with endometrial cancer susceptibility: a meta-analysis

Epidemiological studies have investigated the association between MDM2 promoter SNP 309 (T/G) and endometrial cancer susceptibility. However, the results are still controversial. To obtain a more precise estimate of the relationship, we conducted a meta-analysis of 1,001 cases and 1,889 controls from 6 published case-control studies (one of five articles contains two studies) to estimate the effect of SNP309 on endometrial cancer risk. The strength of association between MDM2 SNP309 and endometrial cancer susceptibility was assessed by calculating pooled odds ratios (ORs) with 95% confidence intervals (CIs). When all the eligible studies were pooled in the meta-analysis, we found that elevated endometrial cancer risk was significantly associated with GG variant genotype, however, heterozygous genotype TG seemed to be only a minor modifier on endometrial cancer risk (for GG vs. TT, OR?=?1.54, 95% CI?=?1.21-1.95, P?=?0.0004; for TG vs. TT, OR?=?0.96, 95% CI?=?0.81-1.14, P?=?0.66; for dominant model, OR?=?1.09, 95% CI?=?0.93-1.29, P?=?0.29; for recessive model, OR?=?1.65, 95% CI?=?1.33-2.04, P?相似文献   

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.     

Association of XPC Polymorphisms and Lung Cancer Risk: A Meta-Analysis

Background

Xeroderma pigmentosum complementation group C gene (XPC) is a key member of nucleotide excision repair pathway and plays an important role in human DNA repair system. It is reported that several common polymorphisms of XPC are associated with susceptibility to lung cancer. However, the conclusion is still elusive.

Method

This meta-analysis was performed to determine the relationship between XPC polymorphisms (Lys939Gln, Ala499Val, and PAT) and lung cancer risk. Published literatures were identified by searching online databases and reference lists of relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association strength. Publication bias were detected by Egger’s and Begg’s test.

Result

After strict screening, we identified 14 eligible studies in this meta-analysis, including 5647 lung cancer cases and 6908 controls. By pooling all eligible studies, we found that the homozygote Gln939Gln genotype was associated with a significantly increased risk of lung cancer in Asian population (GlnGln vs LysLys, OR = 1.229, 95% CI: 1.000–1.510; GlnGln vs LysLys/LysGln, OR = 1.257, 95% CI: 1.038–1.522). As for the PAT polymorphism, in Caucasian population, we found carriers of the −/− genotype were associated significantly reduced risk of lung cancer in homozygote comparison model (−/− vs +/+, OR = 0.735, 95% CI: 0.567–0.952).

Conclusion

In this meta-analysis we found that Gln939Gln genotype was associated with significantly increased risk of lung cancer in Asian population; the PAT −/− genotype significantly reduced susceptibility to lung cancer in Caucasian population; while the XPC Ala499Val polymorphism was not associated with lung cancer risk.     

Association between the TERT Genetic Polymorphism rs2853676 and Cancer Risk: Meta-Analysis of 76 108 Cases and 134 215 Controls

Background

Several recent studies have identified that the TERT genetic polymorphism rs2853676 is associated with cancer risk, but presented inconsistent results. We investigated these inconclusive results by performing a meta-analysis to systematically evaluate the association.

Methods

We conducted a search in PubMed, Google Scholar and ISI Web of Science to select studies on the association between TERT rs2853676 and cancer risk. We conducted a stratified analysis using cancer type, ethnicity and source of controls. We calculated the odds ratios (OR) and 95% confidence intervals (CI). Article quality, heterogeneity, sensitivity, publication bias and statistical power were also assessed.

Results

26 articles covering 76 108 cases and 134 215 controls met our inclusion criteria. A significant association between TERT rs2853676 allele A and cancer susceptibility was demonstrated under a per-allele risk analysis (OR = 1.08, 95% CI = 1.04-1.13). Stratification analysis revealed an increased cancer risk in subgroups of glioma, lung cancer and ovarian cancer. No significant increase was found in melanoma, breast cancer, pancreatic cancer and colorectal cancer. In a subgroup analysis of lung cancer, a statistically significant increase was only observed in adenocarcinoma. Moreover, a stratified analysis performed for ethnic groups revealed that the significant increase was only observed in Caucasians, whereas a non-significant increase was found in Asians.

Conclusions

This meta-analysis suggests that the TERT genetic polymorphism rs2853676 is associated with increased risk of glioma, lung adenocarcinoma and ovarian cancer among Caucasians. Further functional studies are warranted to validate this association and investigate further.     

Association between CYP1A1 Ile462Val Variation and Acute Leukemia Risk: Meta-Analyses Including 2164 Cases and 4160 Controls

Background

Previously, CYP1A1 Ile462Val polymorphism has been indicated to be a risk factor for several malignancies. Increasing reports have focused on the association of CYP1A1 Ile462Val polymorphisms with susceptibility to acute leukemia and have generated controversial results. The goal of the present study was to derive a more precise estimation of the relationship.

Methods

Relevant literature has been rigorously searched and screened. Eligible studies were identified for the period up to Apr 2012. Meta-analyses evaluating the association of CYP1A1 Ile462Val variation with acute leukemia were carried out. Subgroup analyses on ethnicity, clinical types and source of controls were further performed.

Results

A total of thirteen publications including fourteen case-control studies with 2164 cases and 4160 controls were selected for analysis. The overall data indicated a significant association of CYP1A1 Ile462Val polymorphism with acute leukemia risk (Val/Val vs Ile/Ile OR = 1.49; 95% CI = 1.11–1.98; dominant model: OR = 1.26; 95% CI = 1.05–1.51; recessive model: OR = 1.38; 95% CI = 1.04–1.83). In subgroup analysis on ethnicity, increased risk was shown among mixed ethnicities (Val/Val vs Ile/Ile: OR = 2.36; 95% CI = 1.46–3.82; dominant model: OR = 1.37; 95% CI = 1.01–1.86; recessive model: OR = 2.20; 95% CI = 1.37–3.53) but not Asians or Caucasians. In subgroup analysis on clinical types, increased risk was observed in the acute lymphocytic leukemia (ALL) subgroup (Val/Val vs Ile/Ile: OR = 2.06; 95% CI = 1.42–3.01; recessive model: OR = 1.91; 95% CI = 1.32–2.76) but not in the acute myeloid leukemia (AML) subgroup.

Conclusion

The results of the present study suggest that CYP1A1 Ile462Val polymorphism might be a low-penetrant risk factor for acute leukemia. Subgroup analyses suggest that homozygous Val/Val alleles might modify the susceptibility to ALL.     

Association of GSTM1 Null Allele with Prostate Cancer Risk: Evidence from 36 Case-Control Studies

Background

Glutathione S-transferase M1 (GSTM1) is thought to be involved in detoxifying several carcinogens and may play a vital role in tumorigenesis. Numerous studies have evaluated the association between GSTM1 null/present polymorphism and risk of prostate cancer (PCa). However, the results remain inconsistent. To derive a more precise estimation, we performed a meta-analysis.

Methodology/Principal Findings

A comprehensive search was conducted to identify all eligible case-control studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. The overall association was significant (OR = 1.28, 95% CI: 1.11–1.48, P = 0.001). Moreover, subgroup analyses showed GSTM1 null genotype significantly associated with PCa risk among Asians (OR = 1.35, 95% CI: 1.03–1.78, P = 0.03) but not among Caucasians (OR = 1.12, 95% CI: 0.96–1.31, P = 0.16). In addition, we did not find that smoking modified the genotype effect on the risk of PCa.

Conclusions/Significance

The present meta-analysis suggested that GSTM1 null allele was a low-penetrant risk factor for PCa among Asians.     

A Functional Copy-Number Variation in MAPKAPK2 Predicts Risk and Prognosis of Lung Cancer

Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) may promote cancer development and progression by inducing tumorigenesis and drug resistance. To assess whether the copy-number variation g.CNV-30450 located in the MAPKAPK2 promoter has any effect on lung cancer risk or prognosis, we investigated the association between g.CNV-30450 and cancer risk in three independent case-control studies of 2,332 individuals with lung cancer and 2,457 controls and the effects of g.CNV-30450 on cancer prognosis in 1,137 individuals with lung cancer with survival data in southern and eastern Chinese populations. We found that those subjects who had four copies of g.CNV-30450 had an increased cancer risk (odds ratio = 1.94, 95% confidence interval [CI] = 1.61–2.35) and a worse prognosis for individuals with lung cancer (with a median survival time of only 9 months) (hazard ratio = 1.47, 95% CI = 1.22–1.78) compared with those with two or three copies (with a median survival time of 14 months). Meanwhile, four copies of g.CNV-30450 significantly increased MAPKAPK2 expression, both in vitro and in vivo, compared with two or three copies. Our study establishes a robust association between the functional g.CNV-30450 in MAPKAPK2 and risk as well as prognosis of lung cancer, and it presents this functional copy-number variation as a potential biomarker for susceptibility to and prognosis for lung cancer.     

Association between XRCC1 and XRCC3 Polymorphisms with Lung Cancer Risk: A Meta-Analysis from Case-Control Studies

Many studies have reported the association of X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln, Arg194Trp, Arg280His, −77T>C, and X-ray repair cross-complementing group 3 (XRCC3) T241M polymorphisms with lung cancer risk, but the results remained controversial. Hence, we performed a meta-analysis to investigate the association between lung cancer risk and XRCC1 Arg399Gln (14,156 cases and 16,667 controls from 41 studies), Arg194Trp (7,426 cases and 9,603 controls from 23 studies), Arg280His (6,211 cases and 6,763 controls from 16 studies), −77T>C (2,487 cases and 2,576 controls from 5 studies), and XRCC3 T241M (8,560 cases and 11,557 controls from 19 studies) in different inheritance models. We found that −77T>C polymorphism was associated with increased lung cancer risk (dominant model: odds ration [OR] = 1.45, 95% confidence interval [CI] = 1.27–1.66, recessive model: OR = 1.73, 95% CI = 1.14–2.62, additive model: OR = 1.91, 95% CI = 1.24–1.94) when all the eligible studies were pooled into the meta-analysis. In the stratified and sensitive analyses, significantly decreased lung cancer risk was observed in overall analysis (dominant model: OR = 0.83, 95% CI = 0.78–0.89; recessive model: OR = 0.90, 95% CI = 0.81–1.00; additive model: OR = 0.82, 95% CI = 0.74–0.92), Caucasians (dominant model: OR = 0.82, 95% CI = 0.76–0.87; recessive model: OR = 0.89, 95% CI = 0.80–0.99; additive model: OR = 0.81, 95% CI = 0.73–0.91), and hospital-based controls (dominant model: OR = 0.81, 95% CI = 0.76–0.88; recessive model: OR = 0.89, 95% CI = 0.79–1.00; additive model: OR = 0.80, 95% CI = 0.71–0.90) for XRCC3 T241M. In conclusion, this meta-analysis indicates that XRCC1 −77T>C shows an increased lung cancer risk and XRCC3 T241M polymorphism is associated with decreased lung cancer risk, especially in Caucasians.     

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.     

Genetic Association Between AGPHD1 Variant and Lung Cancer Risk

The knowledge of molecular mechanism that underlies the genetic predisposition to lung cancer is yet limited. Results from previous studies addressing the association of AGPHD1 variant rs8034191 with lung carcinogenesis remain inconclusive. Herein, we combined these data and re-examined the association. We performed a meta-analysis of Asian studies identified through various ways. Using the data collected from each eligible study, we combined the effect estimates (ORs and its 95 % CIs) with the fixed effects model (Mantel–Haenszel method). Statistical analyses were done using STATA software. Data from nine studies (29,290 subjects) carried out in Asian populations were analyzed in this work. There was no overall association between variant rs8034191 and lung cancer risk under the allele frequency model (OR = 1.03, 95 % CI = 0.93–1.13, Pheterogeneity = 0.522). We observed the same associations under other genetic models and in the subgroup analyses by ethnicity and smoking status. Our results indicate that variant rs8034191 in the AGPHD1 gene may not modify the genetic risk of lung cancer in Asian populations.     

MTHFR 677C>T Polymorphism and the Risk of Breast Cancer: Evidence from an Original Study and Pooled Data for 28031 Cases and 31880 Controls

Background

Methylenetetrahydrofolate reductase (MTHFR) acts at an important metabolic point in the regulation of cellular methylation reaction. It assists in the conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The latter aids in remethylation of homocysteine to de novo methionine that is required for DNA synthesis. The objective of this study was to examine the effect of MTHFR 677 C>T polymorphism on the risk of breast cancer in the Indian sub-continent.

Methods and Results

We genotyped 677 C>T locus in 1096 individuals that were classified into cases (N=588) and controls (N=508). Genotype data were analyzed using chi-square test. No significant difference was observed in the distribution of genotypes between cases and controls in north Indian (P = 0.932), south Indian (P = 0.865), and pooled data (P = 0.680). To develop a consensus regarding the impact of 677C>T polymorphism on breast cancer risk, we also conducted a meta-analysis on 28031 cases and 31880 controls that were pooled from sixty one studies. The overall summary estimate upon meta-analysis suggested no significant correlation between the 677C>T substitution and breast cancer in the dominant model (Fixed effect model: OR = 0.97, P=0.072, Random effects model: OR = 0.96, P = 0.084) or the recessive model (Fixed effect model: OR = 1.05, P = 0.089; Random effects model: OR= 1.08, P= 0.067).

Conclusion

677 C>T substitution does not affect breast cancer risk in the Indo-European and Dravidian populations of India. Analysis on pooled data further ruled out association between the 677 C>T polymorphism and breast cancer. Therefore, 677 C>T substitution does not appear to influence the risk of breast cancer.