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


Background: The human homologue of the mouse double minute 2 (MDM2) gene is a negative regulator ofTp53. MDM2-309T>G a functional promoter polymorphism was found to be associated with overexpressionthereby attenuation of Tp53 stress response and increased cancer susceptibility. We have planned to evaluate thepossible 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 theMDM2-309T>G polymorphism through the tetra-primer amplification refractory mutation system (ARMS)-PCRmethod. In order to assess the functional relationship of -309T>G SNP with MDM2 expression level, we quantifiedMDM2 mRNA in 30 primary AML blood samples through quantitative RT-PCR. Both the (-309T>G) genotypesand the MDM2 expression were correlated with disease free survival (DFS) rates among patients who haveachieved complete remission (CR) after first induction chemotherapy.
Results: MDM2-309T>G polymorphismwas significantly associated with AML development (p<0.0001). The presence of either GG genotype or G alleleat 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) increasedAML 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, MDM2expression was also found to be significantly elevated in GG genotype patients (p=0.0039) and among CR+vecases (p=0.0036).
Conclusions: The MDM2-309T>G polymorphism might be involved in AML development andalso serve as a good prognostic indicator.