Dataset Information

Lack of an Association between a Functional Polymorphism in the MDM2 Promoter and Breast Cancer in Women in Northeast Iran.

ABSTRACT: BACKGROUND:Breast cancer is one of the most common cancers among women worldwide. Tumor protein 53 (TP53) and its regulator, the mouse double murine 2 (MDM2) protein homologue, influence tumorigenesis through their key roles in cell division and response to DNA damage. The MDM2 SNP309T>G (rs2279744) polymorphism in the promoter region of the MDM2 can cause dysfunction and inactivation of TP53, which promotes tumor progression. The aim of this study was to investigate the possible association between this polymorphism and breast cancer in a northeastern Iranian population. METHODS:A case-control study with 128 female breast cancer patients and 143 healthy women was conducted. PCR-ARMS was performed to assess the MDM2 SNP309T>G (rs2279744) polymorphism. RESULTS:No significant association was found between the GG genotype or G allele polymorphisms and breast cancer in patients or controls (p = 0.116, OR [95% CI]: 1.267 [0.616, 2.603] and p= 0.143, OR [95% CI]: 1.326 [0.908, 1.935], respectively). For the G allele polymorphism, a significant difference of 8 years in the average cancer diagnosis age was observed between TT and TG carriers (40.57 vs. 48.15 years, respectively, p = 0.029). CONCLUSION:The SNP309T>G polymorphism in MDM2 may not be associated with breast cancer in this Iranian population.

SUBMITTER: Tavakkol Afshari Z

PROVIDER: S-EPMC5643450 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Lack of an Association between a Functional Polymorphism in the <i>MDM2</i> Promoter and Breast Cancer in Women in Northeast Iran.

Tavakkol Afshari Zeinab Z Nikpoor Amin Reza AR Tavakkol Afshari Jalil J Ganjali Rashin R Sanglakh Ghoochan Atigh Parvaneh P Homaei Shandiz Fatemeh F Jamialahmadi Khadijeh K

Reports of biochemistry & molecular biology 20171001 1

<h4>Background</h4>Breast cancer is one of the most common cancers among women worldwide. Tumor protein 53 (TP53) and its regulator, the mouse double murine 2 (MDM2) protein homologue, influence tumorigenesis through their key roles in cell division and response to DNA damage. The <i>MDM2</i> SNP309T>G (rs2279744) polymorphism in the promoter region of the MDM2 can cause dysfunction and inactivation of TP53, which promotes tumor progression. The aim of this study was to investigate the possible ...[more]

PMID: 29090237

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Project description:A single nucleotide polymorphism (SNP) rs2853669 (A>G) in the telomerase reverse transcriptase (TERT) promoter has recently been reported in chr5:1,295,349 T>C (T349C), and was shown to be associated with increased cancer risk and poor survival in a specific population. However, at present, the role of this particular SNP with TERT promoter driver mutations and its genetic association with human papilloma virus (HPV) in patients with cervical cancer has not been determined. In the present study, the genetic association of the functional SNP rs2853669 in the presence/absence of TERT promoter hotspot mutations and HPV in patients with cervical cancer of South Indian origin was evaluated. To understand and compare the frequency of the variant allele and its risk association in different cancer types of various populations, the SNP was genotyped in 257 cervical cancer samples and 295 controls, and its associations with TERT promoter hotspot mutations and HPV were analyzed. Furthermore, an extensive search of previously published articles in PubMed, Embase and Web of Science was conducted; a meta-analysis was carried out to elucidate the association of the SNP with different cancer types in global populations. The SNP analysis showed significantly high frequency (41%) of homozygous variant allele rs2853669 (GG) in patients with cervical cancer compared with control samples [Recessive allele model odds ratio (OR)=1.71; 95% CI=1.20-2.43; P=0.003]. No significant interaction was observed between the TERT SNP rs2853669 and HPV status as well as other hotspot TERT promoter (C228T and C250T) mutations determined in our previous study. In addition, the overall meta-analysis revealed a significant association of the SNP rs2853669 with other cancer types in different ethnic populations (OR=1.09; 95% CI=1.03-1.16; P=0.004). The present results suggested that the TERT SNP rs2853669 could play an important role in the risk of cervical cancer in a South Indian population.

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

Lack of an Association between a Functional Polymorphism in the MDM2 Promoter and Breast Cancer in Women in Northeast Iran.

Publications

Lack of an Association between a Functional Polymorphism in the <i>MDM2</i> Promoter and Breast Cancer in Women in Northeast Iran.

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