• Asian Pacific Journal of Cancer Prevention
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• 제15권16호
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• pp.6767-6772
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• 2014

Several studies have suggested associations between MDM2 (mouse double minute 2 homolog) polymorphisms and leukemia risk, but they reported contradictory results. For better understanding of the effect of MDM2 T309G polymorphism on leukemia risk, we performed a meta-analysis. All eligible studies were identified through a search of PubMed, Web of Science, EMBASE, and Chinese Biomedical Literature (CBM) databases before May 2014. Assessment of associations between the MDM2 T309G polymorphism and leukemia risk was conducted by odds ratios (ORs) and 95% confidence intervals (95% CIs). Finally, a total of 11 publications covering 12 case-control studies with 2, 362 cases and 5, 562 controls concerning MDM2 T309G polymorphism with respect to leukemia were included in the meta-analysis. Significant associations were found between MDM2 T309G polymorphism and leukemia risk in four models in overall populations (G vs T: OR=1.29, 95% CI=1.11-1.49, p=0.001; GG vs TT: OR=1.67, 95% CI=1.21-2.30, p=0.002; GG vs TG/TT: OR=1.56, 95% CI=1.21-2.00, p=0.001; GG/TG vs TT: OR=1.28, 95% CI=1.05-1.57, p=0.015). In the sub-group analysis according to ethnicity, increased leukemia risks were observed in three genetic models among Asians but not Caucasians. In conclusion, the results of our meta-analysis suggest that the MDM2 T309G polymorphism can increase the risk of leukemia, especially among Asian populations.

• Asian Pacific Journal of Cancer Prevention
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• 제16권7호
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• pp.2707-2712
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• 2015

Background: The human homologue of the mouse double minute 2 (MDM2) gene is a negative regulator of Tp53. MDM2-309T>G a functional promoter polymorphism was found to be associated with overexpression thereby attenuation of Tp53 stress response and increased cancer susceptibility. We have planned to evaluate the possible role of MDM2-309T>G polymorphism with risk and response to chemotherapy in AML. Materials and Methods: A total of 223 de novo AML cases and 304 age and sex matched healthy controls were genotyped for the MDM2-309T>G polymorphism through the tetra-primer amplification refractory mutation system (ARMS)-PCR method. In order to assess the functional relationship of -309T>G SNP with MDM2 expression level, we quantified MDM2 mRNA in 30 primary AML blood samples through quantitative RT-PCR. Both the (-309T>G) genotypes and the MDM2 expression were correlated with disease free survival (DFS) rates among patients who have achieved complete remission (CR) after first induction chemotherapy. Results: MDM2-309T>G polymorphism was significantly associated with AML development (p<0.0001). The presence of either GG genotype or G allele at MDM2-309 confered 1.79 (95% CI: 1.12-2.86; p<0.001) and 1.46 fold (95%CI: 1.14-1.86; p= 0.003) increased AML risk. Survival analysis revealed that CR+ve cases with GG genotype had significantly increased DFS rates (16months, p=0.05) compared to CR+ve TT (11 months) and TG (9 months) genotype groups. Further, MDM2 expression was also found to be significantly elevated in GG genotype patients (p=0.0039) and among CR+ve cases (p=0.0036). Conclusions: The MDM2-309T>G polymorphism might be involved in AML development and also serve as a good prognostic indicator.

• Asian Pacific Journal of Cancer Prevention
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• 제13권9호
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• pp.4315-4320
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• 2012

Background: The P53 tumor suppressor gene plays a pivotal role in maintaining cellular homeostasis by preventing the propagation of genome mutations. P53 in its transcriptionally active form is capable of activating distinct target genes that contribute to either apoptosis or growth arrest, like P21. However, the MDM2 gene is a major negative regulator of P53. Single nucleotide polymorphisms (SNP) in codon Arg72Pro of P53 results in impairment of the tumor suppressor activity of the gene. A similar effect is caused by a SNP in codon 31 of P21. In contrast, a SNP in position 309 of MDM2 results in increased expression due to substitution of thymine by guanine. All three polymorphisms have been associated with increased risk of tumorigenesis. Aim of the study: We aimed to study the prevalence of SNPs in the P53 pathway involving the three genes, P53, P21 and MDM2, among acute myeloid leukemia (AML) patients and to compare it to apparently normal healthy controls for assessment of impact on risk. Results: We found that the P21 ser31arg heterozygous polymorphism increases the risk of AML (P value=0.017, OR=2.946, 95% CI=1.216-7.134). Although the MDM2 309G allele was itself without affect, it showed a synergistic effect with P21 ser/arg polymorphism (P value=0.003, OR=6.807, 95% CI=1.909-24.629). However, the MDM2 309T allele abolish risk effect of the P21 polymorphic allele (P value=0.71). There is no significant association of P53 arg72pro polymorphism on the risk of AML. Conclusion: We suggest that SNPs in the P53 pathway, especially the P21 ser31arg polymorphism and combined polymorphisms especially the P21/MDM2 might be genetic susceptibility factors in the pathogenesis of AML.

• Asian Pacific Journal of Cancer Prevention
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• 제13권9호
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• pp.4327-4330
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• 2012

The mouse double minute 2 (MDM2) gene plays a key role in the p53 pathway, and the SNP 309T/G single-nucleotide polymorphism in the promoter region of MDM2 has been shown to be associated with increased risk of cancer. However, no consistent results were found concerning the relationships between the polymorphism and prostate cancer risk. This meta-analysis, covering 4 independent case-control studies, was conducted to better understand the association between MDM2-SNP T309G and prostate cancer risk focusing on overall and subgroup aspects. The analysis revealed, no matter what kind of genetic model was used, no significant association between MDM2-SNP T309G and prostate cancer risk in overall analysis (GT/TT: OR = 0.84, 95%CI = 0.60-1.19; GG/TT: OR = 0.69, 95%CI = 0.43-1.11; dominant model: OR = 0.81, 95%CI= 0.58-1.13; recessive model: OR = 1.23, 95%CI = 0.95-1.59). In subgroup analysis, the polymorphism seemed more likely to be a protective factor in Europeans (GG/TT: OR = 0.52, 95%CI = 0.31-0.87; recessive model: OR = 0.58, 95%CI = 0.36-0.95) than in Asian populations, and a protective effect of the polymorphism was also seen in hospital-based studies in all models (GT/TT: OR = 0.74, 95%CI = 0.57-0.97; GG/TT: OR = 0.55, 95%CI = 0.38-0.79; dominant model: OR = 0.69, 95%CI = 0.54-0.89; recessive model: OR = 0.70, 95%CI = 0.51-0.97). However, more primary studies with a larger number of samples are required to confirm our findings.

• Asian Pacific Journal of Cancer Prevention
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• 제14권11호
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• pp.6649-6651
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• 2013

Background: Mdm2 binds to the amino-terminus of p53 to induce its degradation and a single nucleotide polymorphism in the MDM2 promoter region (T309G) has been reported to increase the risk of several carcinomas, such as gastric cancer. However, the results of published studies to analyze the association between MDM2 T309G and gastric cancer havve often conflicted. Methods: To better illustrate the filiation between MDM2 T309G and gastric cancer, we performed a meta-analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the relationship. The pooled ORs were performed for 4 models, additive, recessive, co-dominant model, and dominant. Results: Nine published case-control studies including 3,225 gastric cancer cases and 4,118 controls were identified. The MDM2 T309G 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=1.57; 95%CI=1.57-2.12; p=0.003) and GG versus GT/TT, OR=1.52; 95%CI=1.217-1.90; p<0.001). Furthermore, Egger's test did not show any evidence of publication bias (P = 0.608 for GG versus TT). Conclusion: Our results suggest that the MDM2 T309G polymorphism is indeed associated with a significantly increased risk of gastric cancer.

• Asian Pacific Journal of Cancer Prevention
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• 제13권6호
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• pp.2841-2846
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• 2012

Background: Many studies have investigated the association between the MDM2 promoter SNP309 T/G polymorphism 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 liver cancer in humans and estimated summary odds ratio (OR) with 95% confidence intervals (95% CI) to assess the possible association in a meta-analysis. Results: The main analysis revealed no significant heterogeneity, and the pooled ORs of fixed-effects were all significant (for G versus T, OR = 1.59, 95% CI 1.42-1.78; for GG versus TT, 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 associations to remain significant. Conclusion: The present meta-analysis of available data showed a significant association between the MDM2 SNP309 T/G polymorphism and liver cancer risk, the MDM2 SNP309 G allele contributing to increased risk in both Asians and Caucasians in a graded, dose-dependent fashion.

• Asian Pacific Journal of Cancer Prevention
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• 제17권3호
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• pp.1057-1060
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• 2016

Background: The tumor suppressor p53 is as a regulator of cell proliferation, apoptosis and many other biological processes as well as external and internal stress responses. Mdm2 SNIP309 is a negative regulator of 53. Therefore, this study aimed to determine the role of the Mdm2 SNIP 309 polymorphism in the gastric mucosal morphological patterns in patients with Helicobacter pylori associated gastritis. Materials and Methods: A prospective cross-sectional study was carried out from November 2014 through November 2015. Biopsy specimens were obtained from patients and infection was proven by positive histology. Gastric mucosa specimens were sent to the Molecular Genetics Unit, Institute of Medicine, Suranaree University of Technology where they were tested by molecular methods to detect the patterns of Mdm2 SNIP 309 polymorphism using the real-time PCR hybridization probe method. The results were analyzed and correlated with gastric mucosal morphological patterns by using C-NBI endoscopy. Results: A total of 300 infected patients were enrolled and gastric mucosa specimens were collected. In this study the percentage of Mdm2 SNIP 309 T/T homozygous and Mdm2 SNIP309 G/T heterozygous was 78% and 19 % respectively whereas Mdm2 SNIP309 G/G homozygous was 3%. Mdm2 SNIP 309 T/T homozygous and Mdm2 SNIP309 G/T heterozygosity correlated with type 1 to type 3 gastric mucosal morphological patterns (P<0.01) whereas Mdm2 SNIP309 G/G homozygous correlated with type 4 and type 5 (P<0.01). Conclusions: Our study finds the frequency of Mdm2 SNIP309 G/G in a Thai population is very low, and suggests that this can explain ae Thailand enigma. Types 1 to type 3 are the most common gastric mucosal morphological patterns according to the unique genetic polymorphism of MDM2 SNIP 309 in the Thai population.

• Genomics & Informatics
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• 제18권1호
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• pp.9.1-9.5
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• 2020

Ulcerative colitis is a form of inflammatory bowel disease characterized by chronic inflammation of the colon and rectum. The abnormal lesions in the digestive system caused by ulcerative colitis and intermittent colitis are of major clinical importance. MDM2 is a phospho-protein that functions as a ubiquitin ligase for p53. Recently, a T>G substitution in the promoter of the MDM2 gene (rs309) has been identified. In this case-control study, 174 ulcerative colitis biopsy samples and 82 control samples were collected from colonoscopy centers, hospitals, and clinics in Mazandaran and Gilan Provinces in Iran from October 2014 to May 2015. This MDM2 polymorphism was investigated in DNA samples (extracted from biopsy samples) by amplification-refractory mutation system polymerase chain reaction. The mean age of patients with ulcerative colitis was 46.5 years (range, 28 to 69 years) and that of control individuals was 45.3 years (range, 26 to 71 years). Seventy-eight patients (44.82%) were men and 96 (55.18%) were women. The distribution of the TT, TG, and GG genotypes was 17.93%, 27.59%, and 34.48%, respectively, in the ulcerative colitis patients and 31.70%, 24.40%, and 43.90%, respectively, in the control individuals (odds ratio of GG for ulcerative colitis, 7.142; 95% confidence interval, 2.400 to 9.542; p = 0.001). It was found that a single-nucleotide polymorphism at rs309 in the MDM2 gene was associated with ulcerative colitis. A direct relationship was found between age and ulcerative colitis, while no relationship was found with sex. This finding is of note because the occurrence of intestinal inflammation and subsequent ulcers can precede the development of cancer.

• Asian Pacific Journal of Cancer Prevention
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• 제16권9호
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• pp.4057-4060
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• 2015

Cigarette smoke contains oxidants and free radicals which are carcinogens that can induce mutations in humans. Single nucleotide polymorphisms (SNPs) are the most frequent genetic alterations found in the human genome. In the present study, we have examined the ability of the murine double minute 2 (Mdm2) (rs769412) A>G polymorphism in cigarette smokers to predict risk of cancers. Our results showed that of smokers, 87% were found with AA genotype, 10% with heterozygous AG genotype, and 3% with GG genotype. The heterozygous AG genotype was observed in a lower percentage of smokers (10%) as compared to non-smokers (18%), whereas, homozygous AA genotype was observed in lower percentage of non-smokers (81%) as compared to the smokers (87%). The results from present study support the association with an allele and AG genotype in non-smokers. However, further studies are required to establish the role of Mdm2 (rs769412) C>T in cigarettes smokers and diseases.

• Asian Pacific Journal of Cancer Prevention
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• 제15권13호
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• pp.5277-5281
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• 2014

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 the corresponding 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 the recessive 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.