<i>MDM2</i> Promoter Polymorphism SNP309 Contributes to Tumor Susceptibility: Evidence from 21 Case-Control Studies

Hu, Zhibin; Jin, Guangfu; Wang, Lu; Chen, Feng; Wang, Xinru; Shen, Hongbing

doi:10.1158/1055-9965.epi-07-0634

Cited by 100 publications

(118 citation statements)

References 47 publications

Supporting

Mentioning

102

Contrasting

Unclassified

Order By: Relevance

“…7 On the other hand, our finding of a weak negative association of the MDM2 G allele is in contrast with reports of its preferential transmission to RB patients, 13 modifier role in Li-Fraumeni syndrome 9,19 and association with common cancers. 20 Nevertheless, our findings seem plausible, considering that the association only holds in p53-mutated cancers. 20 If confirmed in other independent studies, the pattern we report here of positive association of p53 Pro/Pro and negative association of MDM2 GG would depict a new scenario with different functional and therapeutic implications.…”

mentioning

confidence: 63%

See 1 more Smart Citation

p53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma

et al. 2011

View full text Add to dashboard Cite

The tumor suppressor p53 and its negative regulator MDM2 have crucial roles in a variety of cellular functions such as the control of the cell cycle, senescence, genome stability and apoptosis, and are frequently deregulated in carcinogenesis. Previous studies have highlighted the contribution of the common functional polymorphisms p53 p.Arg72Pro and MDM2 309SNP to the risk of both common cancers and Li-Fraumeni syndrome. Their possible role in retinoblastoma has recently been addressed by Casté ra et al, who however only studied the MDM2 309SNP. Here, for the first time, we analyzed both single nucleotide polymorphisms (SNPs) in a case-control study of 111 Italian hereditary retinoblastoma patients. We found a significant association of the p53 Pro/Pro genotype with the disease (odds ratio¼3.58, P¼0.002). The MDM2 309SNP showed a weak negative association of allele G that deserves further investigation. These findings further support the hypothesis that genetic variability of the p53 pathway contributes to the individual susceptibility to retinoblastoma, as shown for Li-Fraumeni syndrome and a variety of non-hereditary cancers. Keywords: hereditary retinoblastoma; MDM2; p53; single nucleotide polymorphisms Retinoblastoma (RB, OMIM#180200), the most common primary intraocular malignancy in children, affecting 1:14 000-1:22 000 live births, is caused by biallelic inactivation of RB1. 1 In about 40% of patients a germline mutation inactivates one allele and a somatic one the second allele (hereditary RB), whereas in non-hereditary RB, both alleles are inactivated somatically. Although most children with hereditary RB show multiple bilateral tumors, a significant proportion of carriers remain unaffected or only develop unilateral tumors, or benign retinomas. 2 Penetrance and expressivity of hereditary RB may depend on the type of inherited mutation, and can vary even within families and among patients with identical mutations. [3][4][5] This indicates a role of modifiers that may affect genome stability to favor the occurrence of somatic mutations, and/or the apoptotic pathway to induce loss or maintenance of the mutated retinoblasts.The p53 pathway, the master control system of these processes, is controlled by a feedback autoregulatory loop in which p53 transcriptionally activates MDM2, that in turn functions as a negative regulator by promoting the proteolytic degradation of p53. Interestingly, this circuit can also target pRB to degradation and in physiological condition controls the cell cycle and apoptosis of the retinal cone precursors, from which the RB cell lineage originates. 6 In RB, p53 is not usually mutated nor is MDM2 amplified. Rather, the expression of MDM2 is highly induced and represses p53, 6 thus leaving ample space for constitutional polymorphism of p53 and/or MDM2 to affect the fate of the RB lineage.The 72Pro allele of p53 single nucleotide polymorphisms (SNP) (p.Arg72Pro, rs1042522:G4C) features a reduced proapototic activity compared with the 72Arg allele, and together with its more effici...

show abstract

mentioning

confidence: 63%

“…20 Nevertheless, our findings seem plausible, considering that the association only holds in p53-mutated cancers. 20 If confirmed in other independent studies, the pattern we report here of positive association of p53 Pro/Pro and negative association of MDM2 GG would depict a new scenario with different functional and therapeutic implications. …”

mentioning

confidence: 63%

p53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma

et al. 2011

View full text Add to dashboard Cite

show abstract

“…[9][10][11][12] A polymorphism replacing arginine (R72) with proline (P72) at position 72 in p53 (codon72 polymorphism, referred to as R72P) has been reported to affect p53 function. 13 It has been shown that R72 increases the affinity of p53 to MDM2, affects its export from the nucleus, and provides increased apoptotic potential.…”

mentioning

confidence: 99%

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

Ohnstad¹,

Castro²,

Sun³

et al. 2012

Cancer

View full text Add to dashboard Cite

BACKGROUND: Relatively few sarcomas harbor TP53 (tumor protein p53) mutations, but in many cases, amplification of MDM2 (murine double minute 2) effectively inactivate p53. The p53 pathway activity can also be affected by normal genetic variation. METHODS: The mutation status of TP53 and expression of MDM2, TP53, and their genetic variants SNP309 and R72P (Arg72Pro) were investigated in 125 sarcoma patient samples and 18 sarcoma cell lines. Association of the different genotypes and gene aberrations with chemotherapy response and survival, as well as response to MDM2 antagonists in vitro was evaluated. RESULTS: Twenty-two percent of the tumors had mutant TP53 and 20% MDM2 gene amplification. Patients with wild-type TP53 (TP53 Wt ) tumors had improved survival (P < .001) and TP53 Wt was an independent prognostic factor (hazard ratio ¼ 0.41; 95% confidence interval ¼ 0.23-0.74; P ¼ .03). Interestingly, there was a trend toward longer time to progression after chemotherapy for tumors with the apoptosis-prone p53 variant R72 (P ¼ .07), which was strongest with doxorubicin/ifosfamide-based regimens (P ¼ .01). Liposarcomas had low R72 frequency (33% versus 56%), but increased levels of MDM2 and MDM4 (51% and 11%, P < .001). MDM2 overexpression on a TP53 Wt background predicted better response to MDM2 antagonist Nutlin-3a, irrespective of R72P or SNP309 status. CONCLUSIONS: Improved survival after chemotherapy was found in patients with TP53 Wt tumors harboring the R72 variant. MDM2 overexpression in TP53 Wt tumors predicted good response to MDM2 antagonists, irrespective of R72P or SNP309 status. Thus, detailed TP53 and MDM2 genotype analyses prior to

show abstract

“…The variant allele has been shown to have increased affinity to the MDM2 transcriptional activator Sp1, resulting in higher levels of MDM2 protein and subsequent attenuation of the p53 pathway. This polymorphism is associated with accelerated tumour formation in both hereditary and sporadic cancers (for a review see Bond and Levine, 2007) and a meta-analysis recently concluded that variant homozygote G/G was associated with a significantly increased risk of all types of tumours (Hu et al, 2007). Its possible effect on anticancer drug response remains to be established, but a recent study comparing cell lines with different MDM2 genotypes revealed a lower sensitivity of the G/G homozygous variant to topoisomerase II-interfering drugs (Nayak et al, 2007).…”

mentioning

confidence: 99%

The association between the T309G polymorphism of the MDM2 gene and sensitivity to anticancer drug is dependent on the p53 mutational status in cellular models

et al. 2009

View full text Add to dashboard Cite

BACKGROUND: We investigated, in the panel of 60 human tumour cell lines of the National Cancer Institute (NCI-60), whether the R72P polymorphism of TP53 and the T309G polymorphism of MDM2 were associated to the in vitro cytotoxicity of anticancer agents, extracted from the NCI database. For validation, the same study was performed independently on a second panel of tumour cell lines, JFCR-45. METHODS: Both SNPs were identified in cell DNA using PCR-RFLP techniques confirmed by direct sequencing and by pyrosequencing. For the analysis of the results, the mutational status of p53 was taken into account. RESULTS: In the NCI-60 panel, the TP53 rare-allele frequency was 32% and the MDM2 rare-allele frequency 39%. The MDM2 alleles were distributed according to Hardy -Weinberg equilibrium whereas this was only found, for the TP53 alleles, in p53 non-mutated cell lines. Comparable results were obtained in the JFCR-45 validation set. The TP53 SNP had low impact on anticancer drug cytotoxicity in either panel. In contrast, the MDM2 gene polymorphism had a major impact on anticancer drug cytotoxicity, essentially in p53 non-mutated cell lines. Presence of the rare allele was associated to significantly higher MDM2 protein expression and to increased sensitivity to DNA-interfering drugs. In the JFCR-45 panel, a similar effect of the MDM2 gene polymorphism was observed, but was less dependent on the p53 mutational status. CONCLUSIONS: We hypothesised that cell lines harbouring the MDM2 G allele presented a lower availability of p53 for DNA repair, translating into higher sensitivity to DNA-damaging agents.

show abstract

MDM2 Promoter Polymorphism SNP309 Contributes to Tumor Susceptibility: Evidence from 21 Case-Control Studies

Cited by 100 publications

References 47 publications

p53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma

p53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

The association between the T309G polymorphism of the MDM2 gene and sensitivity to anticancer drug is dependent on the p53 mutational status in cellular models

Contact Info

Product

Resources

About