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Role of the MDM2 Promoter Polymorphism (-309T>G) in Acute Myeloid Leukemia Development

  • Cingeetham, Anuradha (Department of Genetics, Osmania University) ;
  • Vuree, Sugunakar (Department of Genetics, Osmania University) ;
  • Jiwatani, Sangeeta (Nizam's Institute of Medical Sciences) ;
  • Kagita, Sailaja (Nizam's Institute of Medical Sciences) ;
  • Dunna, Nageswara Rao (School of Chemical and Biotechnology, SASTRA University) ;
  • Meka, Phanni Bhushann (Department of Genetics, Osmania University) ;
  • Gorre, Manjula (Department of Genetics, Osmania University) ;
  • Annamaneni, Sandhya (Department of Genetics, Osmania University) ;
  • Digumarti, Raghunadharao (Nizam's Institute of Medical Sciences) ;
  • Sinha, Sudha (MNJ Institute of Oncology Regional Cancer Center) ;
  • Satti, Vishnupriya (Department of Genetics, Osmania University)
  • Published : 2015.04.14

Abstract

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.

Keywords

AML;MDM2;tetra primer (ARMS) PCR;RT-PCR;disease free survival;complete remission

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