MDM2 T309G has a Synergistic Effect with P21 ser31arg Single Nucleotide Polymorphisms on the Risk of Acute Myeloid Leukemia


Background: The P53 tumor suppressor gene plays a pivotal role in maintaining cellular homeostasis bypreventing the propagation of genome mutations. P53 in its transcriptionally active form is capable of activatingdistinct target genes that contribute to either apoptosis or growth arrest, like P21. However, the MDM2 gene isa major negative regulator of P53. Single nucleotide polymorphisms (SNP) in codon Arg72Pro of P53 results inimpairment 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 byguanine. 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 forassessment of impact on risk.
Results: We found that the P21 ser31arg heterozygous polymorphism increasesthe risk of AML (P value=0.017, OR=2.946, 95% CI=1.216-7.134). Although the MDM2 309G allele was itselfwithout 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: Wesuggest that SNPs in the P53 pathway, especially the P21 ser31arg polymorphism and combined polymorphismsespecially the P21/ MDM2 might be genetic susceptibility factors in the pathogenesis of AML.