MDM2 SNP309 variation contributes to leukemia risk: Meta-analyses based on 7259 subjects

Institute of Cancer, Xinqiao Hospital.
Leukemia & lymphoma (Impact Factor: 2.89). 05/2012; 53(11):2245-52. DOI: 10.3109/10428194.2012.691485
Source: PubMed


Abstract Evidence implicates MDM2 (murine double minute-2) T309G polymorphism as a risk factor for several cancers. Increasing numbers of studies have been carried out on the association of MDM2 T309G polymorphism with susceptibility to leukemia and have generated conflicting results. The aim of the present study was to derive a more precise estimation of the relationship. Meta-analyses assessing the association of MDM2 T309G variation with leukemia were conducted. Separate analyses on ethnicity and clinical types were also performed. Eligible studies were identified for the period up to February 2012. Consequently, seven publications including eight case-control studies with 1777 cases and 5482 controls were selected for analysis. The overall data indicated a significant association of the MDM2 T309G polymorphism with leukemia risk (GG vs. TT: odds ratio [OR] = 1.62; 95% confidence interval [CI] = 1.14-2.29; dominant model: OR = 1.20; 95% CI = 1.06-1.36; recessive model: OR = 1.47; 95% CI = 1.07-2.03). In subgroup analysis by ethnicity, the G allele may increase leukemia susceptibility among Asians (GG vs. TT: OR = 3.06; 95% CI = 2.05-4.56; dominant model: OR = 1.82; 95% CI = 1.31-2.51; recessive model: OR = 2.32; 95% CI = 1.69-3.19) but not Caucasians. In subgroup analysis by clinical types, data suggested increased risk for acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) under additive and recessive models, respectively. Similarly, elevated risk for chronic lymphocytic leukemia (CLL) was shown under the dominant model. Collectively, the results of the present study suggest that MDM2 T309G polymorphism might be a low-penetrant risk factor for leukemia among Asians but not Caucasians. The G allele might increase CLL susceptibility and homozygous GG might elevate AML and CML risk.

21 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: ABSTRACT To evaluate the contribution of association studies of candidate polymorphisms to inherited predisposition to chronic lymphocytic leukemia (CLL) we conducted a systematic review and meta-analysis of published case-control studies. We identified 36 studies which reported on polymorphic variation in 19 genes and CLL risk. Out of the 23 polymorphic variants, significant associations (P <0.05) were seen in pooled analyses for only four variants: MDR1- rs1045642; LTA, rs2239704; CD38- rs6449182 and IFNGR1- rs4896243. These findings should be interpreted cautiously as the estimated false-positive report probabilities (FPRP) for each association were not noteworthy (i.e. FPRP>0.2). While studies of candidate polymorphisms may be an attractive means of identifying risk factors for CLL, the limited power of published studies to demonstrate statistically significant associations makes it is essential that future analyses be based on sample sizes well-powered to identify variants having modest effects on CLL risk.
    Leukemia & lymphoma 05/2013; 55(1). DOI:10.3109/10428194.2013.800197 · 2.89 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The genetic or functional inactivation of the p53 pathway plays an important role with regards to disease progression from the chronic phase (CP) to blast phase (BP) and imatinib treatment response in chronic myeloid leukemia (CML). Two functional single nucleotide polymorphisms (SNPs), p53 R72P and MDM2 SNP309, are associated with alternation of p53 activity, however the association regarding CML susceptibility and BP transformation under imatinib treatment is unclear. The MDM2 SNP309 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism and confirmed by direct sequencing from 116 CML patients, including 104 in the CP at diagnosis, and 162 healthy Taiwanese controls. The p53 R72P polymorphism was examined in all CML patients. The SNP309 G/G genotype was associated with an increased risk of CML susceptibility (OR: 1.82, 95% CI: 1.03-3.22, P = 0.037), and an earlier age of disease onset (log-rank P = 0.005) compared with the T/T + T/G genotypes. Higher MDM2 mRNA expression was found in G/G genotype compared with T/T (P = 0.034) and T/T + T/G (P = 0.056) genotypes. No associations were found between the p53 R72P genotypes and clinical parameters and survival outcomes. Among 62 CP patients receiving imatinib as first-line therapy, the G/G genotype was associated with a shorter blast-free survival (log-rank P = 0.048) and more clonal evolution compared with the T/T + T/G genotypes. In patients with advanced diseases at diagnosis, the G/G genotype was associated with a poor overall survival (log-rank P = 0.006). Closely monitoring CML patients harboring the G/G genotype and further large-scale studies are warranted. © 2013 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 06/2013; 53(12). DOI:10.1002/mc.22061 · 4.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: TP53 is one of the most important prognostic factors in chronic lymphocytic leukemia (CLL). Modulation of microRNAs by TP53 in CLL pathogenesis has been a hotspot. Besides, it has an intimate association with other cytogenetics and plays an important part in drug resistance of CLL. All above indicate an embedded TP53-centered network in CLL pathogenesis and prognosis. In this review, we focus on the TP53-centered network and its roles in the pathogenesis of CLL.
    International journal of clinical and experimental pathology 07/2013; 6(7):1223-9. · 1.89 Impact Factor
Show more