Abstract
The effect of single nucleotide polymorphisms (SNPs) at MDM2 has been investigated in several cancer types. Three MDM2 SNPs(rs937283, rs2270744 and rs769412) have previously been suggested to be positively correlated with cancer. In this study, we aimed to explore the association of rs937283, rs2270744 and rs769412 polymorphisms with retinoblastoma (RB) risk, clinicopathological characteristics, and prognosis. Compared with wild-type genotype AA at rs937283, individuals carrying AG and GG genotype had a significantly increased risk for developing RB (OR = 1.86, 95% CI 1.13–3.08; OR = 2.48, 95% CI 1.10–5.62, respectively). RB patients with allele G at rs937283 were more susceptible to invasion and high tumor aggression (OR = 2.42, 95% CI 1.43–4.11; OR = 2.15, 95% CI 1.27–3.64, respectively). Kaplan-Meier curves and log-rank results revealed that RB patients harboring genotype GG and G allele at rs937283 had worse survival (P < 0.02 and P < 0.01, respectively). In addition, the A to G substitution at rs937283 significantly enhanced the transcription activity of the MDM2 gene in vitro. In vivo, we found that MDM2 mRNA and protein were overexpressed in individuals who carried the G allele at rs937283. This study suggested that the MDM2 rs937283 polymorphism is a novel functional SNP both in vitro and in vivo as well as a biomarker for poor prognosis in RB.
Highlights
Other than the RB gene, studies have shown that a number of other genes, including p21, p53, MDM2, and MDM4, may influence the development of RB9. p53 pathway is the master control system of cell cycle, genome stability, and cell apoptosis, which could be modulated by a negative feedback loop in which p53 could
Inactivation of the RB1 tumor suppressor gene seems sufficient for the onset of this tumor, the development of RB is potentially modified by the presence of numerous additional genetic mutations in RB patients[8,20]
We evaluated the association between rs769412, rs937283 and rs2279744 polymorphisms at MDM2 on RB risk and prognosis
Summary
Other than the RB gene, studies have shown that a number of other genes, including p21, p53, MDM2, and MDM4, may influence the development of RB9. p53 pathway is the master control system of cell cycle, genome stability, and cell apoptosis, which could be modulated by a negative feedback loop in which p53 could. Recent data suggested that MDM2 gene polymorphisms may contribute to increased MDM2 basal expression and increase cancer susceptibility. MDM2 rs2279744 (SNP T309G) polymorphism has been shown to produce a higher-affinity DNA-binding site for Sp1, which could increase MDM2 mRNA and protein expression, and increase the degradation of p53 and hinder p53-induced apoptosis[13]. Previous studies have found a positive association between MDM2 rs2279744 polymorphism and RB development[9,15]. In addition to rs2279744, recent studies have suggested the potential association of rs769412 and rs937283 in the MDM2 loci with cancer development. Previous studies have reported rs769412 and rs937283 polymorphism were associated with the development of several cancer types[16,18]. We conducted the molecular work to confirm whether the variants could alter MDM2 expression
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