MDM2 promoter SNP309 is associated with an increased susceptibility to chronic lymphocytic leukemia and correlates with MDM2 mRNA expression in Chinese patients with CLL

Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.
International Journal of Cancer (Impact Factor: 5.09). 05/2012; 130(9):2054-61. DOI: 10.1002/ijc.26222
Source: PubMed


A single nucleotide polymorphism (SNP) at position 309 in the promoter region of MDM2 leading to increased expression of MDM2 and attenuated function of p53 has recently been suggested as an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL) although this has been questioned. The MDM2 SNP309 genotypes in 173 CLL patients and 260 healthy controls were detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, which was confirmed by direct DNA sequencing. Compared with the T/T genotype, the SNP309 G/G genotype instead of T/G heterozygote was associated with a significantly increased risk of CLL (OR = 2.84; 95% CI 1.61-5.03; p < 0.001). Age at onset of CLL was similar irrespective of MDM2 status. MDM2 mRNA expression within CLL of G/G genotype was significantly higher than that in T/G (p = 0.009) and T/T genotypes (p < 0.001). Excluding patients with p53 deletions or mutations enhanced the significance of the findings (G/G vs. T/T, p < 0.001; G/G vs. T/G p = 0.001), which prompted us to study the role of the polymorphism in p53 wild-type individuals. In the p53 wild-type groups, survival analysis showed that the patients with MDM2 SNP309 G/G and T/G genotypes both had significantly shorter treatment-free survival (TFS) than SNP309 T/T genotype. Notably, univariate and multivariate analyses showed that MDM2 SNP309 genotypes were associated with TFS. These data show that MDM2 309G polymorphisms contribute to the risk of developing CLL. The unfavorable MDM2 SNP309 G/G genotype was associated with an increase of MDM2 mRNA expression. MDM2 SNP309 was found to be associated with TFS in p53 wild-type Chinese CLL populations.

Download full-text


Available from: Cheng Fang, Dec 31, 2014
16 Reads
  • Source
    • "Whether MDM2 SNP309 polymorphism has a correlation with the prognosis of cancers remains controversial. Evidence indicates that MDM2 SNP309 genetic variation might confer poor outcomes in colorectal cancer and chronic lymphocytic leukemia [69], [70]. However, a study regarding prostate carcinoma failed to reveal such association [71]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Evidence suggests that MDM2 T309G polymorphism may be a risk factor for several cancers. Increasing investigations have been conducted on the association of MDM2 T309G polymorphisms with lung cancer risk and have yielded conflicting results. Previous meta-analyses on this issue have reported inconclusive data. The aim of the present study was to derive a more precise estimation of the relationship. Updated meta-analyses examining the association between MDM2 T309G polymorphism and lung cancer risk were performed. Separate analyses on ethnicity, smoking status, histological types and gender as well as source of controls were also implemented. Eligible studies were identified for the period up to Feb 2012. Lastly, ten publications including eleven case-control studies were selected for analysis. The overall data failed to indicate a significant association between MDM2 T309G polymorphism and lung cancer risk (GG vs TT OR = 1.14; 95%CI = 0.95-1.37; dominant model: OR = 1.05; 95%CI = 0.92-1.19; recessive model: OR = 1.12; 95%CI = 0.99-1.27). In a subgroup analysis by smoking status, increased lung cancer risk was shown among never-smokers (GG vs TT: OR = 1.76; 95%CI = 1.36-2.29; dominant model: OR = 1.48; 95%CI = 1.22-1.81; recessive model: OR = 1.37; 95%CI = 1.11-1.69). In subgroup analysis by gender, elevated risk was presented among women under a recessive model (OR = 1.29; 95%CI = 1.04-1.59). In the subgroup analysis by ethnicity, histological types and source of controls, no marked associations were observed. Compared to the previous meta-analyses, the results of this study confirmed that MDM2 T309G polymorphism might be a risk factor for lung cancer among never-smokers. However, the data failed to suggest a marked association between the G allele of MDM2 T309G and lung cancer risk among Asians. More interestingly, subgroup analysis by gender indicated that homozygous GG alleles might raise lung cancer risk among females.
    PLoS ONE 07/2012; 7(7):e41546. DOI:10.1371/journal.pone.0041546 · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We conducted a multicenter prospective study for evaluating the utility and prognostic markers of recombinant human soluble thrombomodulin (rTM) treatment for acute disseminated intravascular coagulation (DIC) by various types of hematologic malignancies. The study comprised 30 patients with DIC due to hematologic diseases without severe infection. DIC improved in 15 patients and 20 were alive on day 28. Univariate analyses showed that, in comparison with patients who had survived on day 28, patients who had not survived on day 28 showed significantly higher plasma levels of plasminogen activator inhibitor-I (PAI-I) and significantly lower plasma activity of a disintegrin and metalloproteinase with a thrombospondin Type 1 motif, member 13 (ADAMTS-13). Moreover, multivariate logistic regression analysis identified a significant association between plasma ADAMTS-13 activity before treatment and survival on day 28 (P = 0.034). In particular, patients with lower ADAMTS-13 activity (≤65%) had a poorer survival rate than those with a higher activity (P = 0.042). These findings suggest that the plasma ADAMTS-13 activity at the time of DIC diagnosis might help to predict the prognosis of patients treated with rTM for DIC associated with hematologic malignancies. Am. J. Hematol., 2012. © 2011 Wiley-Liss, Inc.
    American Journal of Hematology 01/2012; 87(1):116-9. DOI:10.1002/ajh.22185 · 3.80 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hemophilia B is an inherited bleeding disorder caused by mutations in the F9 gene, located on the X chromosome at position Xq27 [1]. In 1970, Veltkamp et al. described a rare form of hemophilia B, known as hemophilia B Leiden, distinguished by low levels of factor IX ( FIX) in childhood and loss of the hemophilia phenotype following puberty [2,3]. The mechanism of recovery in hemophilia B Leiden is controversial and is the subject of ongoing research. In the present case, we observed an unintended and dramatic rise in FIX levels after anabolic steroid use in a man with hemophilia B Leiden. This case lends additional support to the hypothesis that it is androgen that drives the increase in FIX expression in hemophilia B Leiden.
    American Journal of Hematology 01/2012; 87(1):122-3. DOI:10.1002/ajh.22190 · 3.80 Impact Factor
Show more