Dataset Information

Impact of MDM2 309T>G polymorphism on sarcomagenesis.

ABSTRACT: BACKGROUND:A series of epidemiological studies have attempted to evaluate the impact of 309T>G polymorphism in MDM2 gene frequently identified as a susceptibility loci for various cancers on malignant sarcomas, however the reported conclusions remain inconsistent and elusive. We pooled all usable data sets in order to systematically assess the association between 309T>G polymorphism and sarcoma risk. METHODS:To identify as many informative studies with complete data as possible, we searched a number of databases (PubMed, EBSCO, BIOSIS, the Cochrane Library, ISI Web of Science, Wiley Online Library and Embase). Inclusion criteria were defined to select the eligible studies. The fixed effects meta-analysis was properly used to calculate the pooled ORs and 95% CIs. MAJOR FINDINGS:We eventually identified six studies evaluating the association of sarcoma risk with 309T>G polymorphism. People with 309-GG were found to have 43% greater risk of sarcoma relative to people with 309-TT (OR, 1.43; 95% CI, 1.01~2.03; Pheterogeneity, 0.45). In the G vs. T genetic model, the risk reduced to 19% (OR, 1.19; 95% CI, 1.01~1.40; Pheterogeneity, 0.50). Statistical data showed no significant heterogeneity or publication bias in the meta-analysis. CONCLUSION:These data demonstrate that 309T>G polymorphism located within the MDM2 gene may act as modifier factor for sarcomas. A weakness of this analysis is that the findings cannot be explainable when the subtypes are separated and additional larger investigations are needed to identify the role of 309T>G polymorphism in each form of sarcoma.

SUBMITTER: Liu HW

PROVIDER: S-EPMC4612880 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Impact of MDM2 309T>G polymorphism on sarcomagenesis.

Liu Hua-Wei HW Ni Ming M Li Xiang X Chen Hui H Zhang Guo-Qiang GQ Chai Wei W Xu Meng M Zhou Yong-Gang YG Chen Ji-Ying JY Wang Yan Y

International journal of clinical and experimental medicine 20150815 8

<h4>Background</h4>A series of epidemiological studies have attempted to evaluate the impact of 309T>G polymorphism in MDM2 gene frequently identified as a susceptibility loci for various cancers on malignant sarcomas, however the reported conclusions remain inconsistent and elusive. We pooled all usable data sets in order to systematically assess the association between 309T>G polymorphism and sarcoma risk.<h4>Methods</h4>To identify as many informative studies with complete data as possible, w ...[more]

PMID: 26550195

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Project description:Background and Purpose- The E3 ubiquitin ligase MDM2 (murine double minute 2) is the main negative regulator of the p53 protein-a key player in neuronal apoptosis after ischemia. A functional single-nucleotide polymorphism in the human MDM2 gene promoter (rs2279744) regulates MDM2 protein expression. We investigated whether the MDM2 SNP309, by controlling p53-mediated apoptosis, determines functional outcome after stroke. Methods- Primary cortical neurons were subjected to oxygen and glucose deprivation. Mice were subjected to ischemic (transient middle cerebral artery occlusion) or hemorrhagic (collagenase injection) stroke models. Protein and mRNA levels of MDM2 and p53 were measured in both neuronal and brain extracts. The interaction of MDM2 with p53 was disrupted by neuronal treatment with nutlin-3a. siRNA was used to knockdown MDM2 expression. We analyzed the link between the MDM2 SNP309 and functional outcome, measured by the modified Rankin Scale scores, in 2 independent hospital-based stroke cohorts: ischemic stroke cohort (408 patients) and intracerebral hemorrhage cohort (128 patients). Results- Experimental stroke and oxygen and glucose deprivation induced the expression of MDM2 in the brain and neurons, respectively. Moreover, oxygen and glucose deprivation promoted MDM2 binding with p53 in neurons. Disruption of the MDM2-p53 interaction with nutlin-3a, or MDM2 knockdown by siRNA, triggered p53 accumulation, which increased neuronal susceptibility to oxygen and glucose deprivation-induced apoptosis. Finally, we showed that patients harboring the G allele in the MDM2 promoter had higher MDM2 protein levels and showed better functional outcome after stroke than those harboring the T/T genotype. The T/T genotype was also associated with large infarct volume in ischemic stroke and increased lesion volume in patients with intracerebral hemorrhage. Conclusions- Our results reveal a novel role for the MDM2-p53 interaction in neuronal apoptosis after ischemia and show that the MDM2 SNP309 determines the functional outcome of patients after stroke.

Dataset Information

Impact of MDM2 309T>G polymorphism on sarcomagenesis.

Publications

Impact of MDM2 309T>G polymorphism on sarcomagenesis.

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