A Single Nucleotide Polymorphism in the MDM2 Promoter Attenuates the p53 Tumor Suppressor Pathway and Accelerates Tumor Formation in Humans

Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA.
Cell (Impact Factor: 33.12). 12/2004; 119(5):591-602. DOI: 10.1016/j.cell.2004.11.022
Source: PubMed

ABSTRACT The tumor suppressor p53 gene is mutated in minimally half of all cancers. It is therefore reasonable to assume that naturally occurring polymorphic genetic variants in the p53 stress response pathway might determine an individual's susceptibility to cancer. A central node in the p53 pathway is the MDM2 protein, a direct negative regulator of p53. In this report, a single nucleotide polymorphism (SNP309) is found in the MDM2 promoter and is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway. In humans, SNP309 is shown to associate with accelerated tumor formation in both hereditary and sporadic cancers. A model is proposed whereby SNP309 serves as a rate-limiting event in carcinogenesis.

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    • "With a major rate of fertilization and implantation, the risk of pregnancy loss from other causes also increases. Moreover, even without full understanding of the effect of the p63 polymorphism on its functioning, it is known that the TT genotype of MDM2 (rs2279744) results in lower levels of the protein [20] and Table 2 TP63, TP73 and MDM2 SNPs: allelic and genotypic frequencies in women with RPL and in the control group. "
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    ABSTRACT: Recent studies have investigated the role of the p53 gene family in reproductive processes. Each member of the gene family acts through different mechanisms: p53 is involved in genomic stability and regulation of blastocyst implantation; p63 acts as a regulator of the quality and maturation of oocytes; and p73 controls the meiotic spindle. Polymorphisms in the genes of the p53 family have been associated with female infertility. One polymorphism in MDM2, the main regulator of the p53 family, has also been associated with this condition. Although polymorphisms in the TP53 gene have been related to recurrent pregnancy loss (RPL), there have been no studies associating polymorphisms in p63 and p73 with RPL. Therefore, the aim of this study was to evaluate the role of polymorphisms in the TP63 (rs17506395), TP73 (rs2273953, rs1801173), and MDM2 (SNP309, rs2279744) genes as risk factors for RPL.
    European Journal of Obstetrics & Gynecology and Reproductive Biology 08/2014; 182C:7-10. DOI:10.1016/j.ejogrb.2014.07.044 · 1.63 Impact Factor
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    • "Beside the TP53 gene and its Arg72Pro polymorphism , MDM2 gene, a negative regulator of the former with the SNP 309 T > G in the promoter region, is associated with hepatocellular carcinoma [16]. This SNP was described for the first time by Bond et al. (2004), to be associated with accelerated tumor formation , and then studied in a multitude of cancers [17] [18]. "
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    ABSTRACT: MDM2 gene polymorphisms 285G/C and 344 T/A are two single nucleotide polymorphisms (SNPs) recently identified as important variants that could influence the expression of MDM2 gene through the modulation of transcription factors binding on the SNP309T/G. The 285C variant seems to present a geographically distinct distribution in humans and to be associated with a low cancer risk. In the present report, we studied the distribution of the three SNPs in a population with low liver cancer incidence. A group of 119 patients with hepatocellular carcinoma (HCC, 63.45 +/- 12.59 year, 26-80) and another of 103 non-HCC controls (56 +/- 10.82 year, 22-79) were enrolled to investigate association between MDM2 polymorphisms and susceptibility to develop HCC. The three studied SNPs (285G/C, 309 T/G and 344 T/A) were genotyped using polymerase chain reaction and sequencing techniques. Genotypes and alleles distributions of the three studied polymorphisms of MDM2 were not significantly different between cases and controls. An increased risk of HCC development was found in case of 309G allele presence albeit without reaching the significance (29.8% vs 22.3%, OR = 1.48, 95% CI, 0.96-2.27, p = 0.073). In addition, neither 285C nor 344A MDM2 variants were significantly associated with an increased risk of HCC (p = 0.688 and p = 1 respectively). Remarkably, we found that the supposedly Caucasian-specific 285C variant was present in 1% of the Moroccan population. This is the first study of the MDM2 SNP285G/C and SNP344T/A polymorphisms in association with HCC development. In contrast with previous studies, showing that females carrying SNP285C variant have a significantly reduced risk of developing breast, ovarian and endometrial cancer, no significant modulation of HCC risk was found in a North-African population.
    Infectious Agents and Cancer 04/2014; 9(1):11. DOI:10.1186/1750-9378-9-11 · 2.07 Impact Factor
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    • "The functional polymorphic variant in the HDM2 promoter at position 309 (rs2279744) have been suggested to affect the transcriptional activator SP1 binding, thereby modulating HDM2 transcription level. The G variant has been shown to increase the affinity for Sp1, resulting in higher levels of HDM2 mRNA and protein and the subsequent attenuation of the TP53 pathway (Bond et al. 2004). The impact of this genetic variation on HDM2 levels have a snow-balling effect on TP53 amounts in the cell, and the G allele which leads to higher HDM2 transcription was shown to attenuate the TP53 response which could alter cellular response to radiation therapy and DNAdamaging drugs (Nayak et al. 2007). "
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    ABSTRACT: Due to individual variations in radiosensitivity, biomarkers are needed to tailor radiation treatment to cancer patients. Since single nucleotide polymorphisms (SNPs) are frequent in human, we hypothesized that SNPs in genes that mitigate the radiation response are associated with radiotoxicity, in particular late complications to radiotherapy and could be used as genetic biomarkers for radiation sensitivity. A total of 155 patients with nasopharyngeal cancer were included in the study. Normal tissue fibrosis was scored using RTOG/EORTC grading system. Eleven candidate genes (ATM, XRCC1, XRCC3, XRCC4, XRCC5, PRKDC, LIG4, TP53, HDM2, CDKN1A, TGFB1) were selected for their presumed influence on radiosensitivity. Forty-five SNPs (12 primary and 33 neighboring) were genotyped by direct sequencing of genomic DNA. Patients with severe fibrosis (cases, G3–4, n = 48) were compared to controls (G0–2, n = 107). Results showed statistically significant (P < 0.05) association with radiation complications for six SNPs (ATM G/A rs1801516, HDM2 promoter T/G rs2279744 and T/A rs1196333, XRCC1 G/A rs25487, XRCC5 T/C rs1051677 and TGFB1 C/T rs1800469). We conclude that these six SNPs are candidate genetic biomarkers for radiosensitivity in our patients that have cumulative effects as patients with severe fibrosis harbored significantly higher number of risk alleles than the controls (P < 0.001). Larger cohort, independent replication of these findings and genome-wide association studies are required to confirm these results in order for SNPs to be used as biomarkers to individualize radiotherapy on genetic basis.
    04/2014; 4(2). DOI:10.1007/s13205-013-0135-3
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