MDM2 SNP309, gene-gene interaction, and tumor susceptibility: an updated meta-analysis

Abstract

BackgroundThe tumor suppressor gene p53 is involved in multiple cellular pathways including apoptosis, transcriptional control, and cell cycle regulation. In the last decade it has been demonstrated that the single nucleotide polymorphism (SNP) at codon 72 of the p53 gene is associated with the risk for development of various neoplasms. MDM2 SNP309 is a single nucleotide T to G polymorphism located in the MDM2 gene promoter. From the time that this well-characterized functional polymorphism was identified, a variety of case-control studies have been published that investigate the possible association between MDM2 SNP309 and cancer risk. However, the results of the published studies, as well as the subsequent meta-analyses, remain contradictory.MethodsTo investigate whether currently published epidemiological studies can clarify the potential interaction between MDM2 SNP309 and the functional genetic variant in p53 codon72 (Arg72Pro) and p53 mutation status, we performed a meta-analysis of the risk estimate on 27,813 cases with various tumor types and 30,295 controls.ResultsThe data we reviewed indicated that variant homozygote 309GG and heterozygote 309TG were associated with a significant increased risk of all tumor types (homozygote comparison: odds ratio (OR) = 1.25, 95% confidence interval (CI) = 1.13-1.37; heterozygote comparison: OR = 1.10, 95% CI = 1.03-1.17). We also found that the combination of GG and Pro/Pro, TG and Pro/Pro, GG and Arg/Arg significantly increased the risk of cancer (OR = 3.38, 95% CI = 1.77-6.47; OR = 1.88, 95% CI = 1.26-2.81; OR = 1.96, 95% CI = 1.01-3.78, respectively). In a stratified analysis by tumor location, we also found a significant increased risk in brain, liver, stomach and uterus cancer (OR = 1.47, 95% CI = 1.06-2.03; OR = 2.24, 95%CI = 1.57-3.18; OR = 1.54, 95%CI = 1.04-2.29; OR = 1.34, 95%CI = 1.07-1.29, respectively). However, no association was seen between MDM2 SNP309 and tumor susceptibility in the stratified analysis by p53 mutation status (GG vs TT: OR = 1.17, 95% CI = 0.75-1.82 and TG vs TT: OR = 1.09, 95% CI = 0.89-1.34 for positive p53 mutation status; GG vs TT: OR = 0.95, 95% CI = 0.72-1.25 and TG vs TT: OR = 1.06, 95% CI = 0.85-1.30 for negative p53 mutation status).ConclusionsThe analyses indicate that MDM2 SNP309 serves as a tumor susceptibility marker, and that there is an association between MDM2 SNP309 and p53 Arg72Pro regarding tumor susceptibility. Further studies that take into consideration environmental stresses and functional genetic variants in the p53-MDM2-related genes are warranted.

Uncommon non-oncogenic HPV genotypes, TP53 and MDM2 genes polymorphisms in HIV-infected women in Southern Brazil

“…10 Studies have shown that a Single Nucleotide Polymorphism (SNP) on promoter region of MDM2 gene, the SNP309 (T to G change on nucleotide 309 of the first intron), results in a higher level of MDM2 mRNA and MDM2 protein, and consequent reduction of the p53 pathway. 11 The SNP309 occurs at a relatively high frequency in the general population, and it was shown that it presents a strong association with HPVmediated cervical carcinogenesis. 12 Based on the presented data, this study aimed to investigate the HPV infection spectrum, to identify the most prevalent genotypes, to determine the frequencies of SNPs Arg72Pro and MDM2 SNP309, and their association with possible risk factors for viral persistence and for the development of pre-neoplastic and neoplastic lesions of the uterine cervix in HIV-infected women.…”

Maternal SNPs in the p53 Pathway: Risk Factors for Trisomy 21?

“…Thus, it is possible that genes that undergo selection in the TP53 pathway may affect human reproduction [29]. The G allele of MDM2 c.14+309T>G SNP is associated with a high risk of spontaneous abortion [16], which supports the combined effect between this MDM2 polymorphism and R72P of p53 [7,58]. The MDM4 gene, that is structurally homologous with the MDM2 gene, is also involved in the regulation of p53.…”

Evaluation of TP53 Pro72Arg and MDM2 SNP285–SNP309 polymorphisms in an Italian cohort of LFS suggestive patients lacking identifiable TP53 germline mutations

“…To this, for the first time in a TP53 negative Italian population of LFS Suggestive patients classified according to the revised Chompret criteria [7], we evaluated the effect of TP53 codon 72 polymorphism, MDM2 SNP309 and MDM2 SNP285 already described as putative genetic determinants in tumour onset, though with debatable results [16,17,34]. In particular, TP53 Pro72Arg has been controversially linked to cancer risk in different studies [14][15][16][17] but its role on TP53-negative patients has never been investigated. The MDM2 SNP309 has been shown to be a modifier factor in TP53 positive LFS patients, but only one previous study [19] focused the attention on a TP53 negative combined Dutch-Finnish population.…”

“…Meta-analyses studies on patients with various tumour types demonstrated that the Pro-Pro genotype is associated with an increased risk of carcinogenesis [16,17]; moreover Khan et al [17] found this effect related to the ethnicity. As a matter of fact, an increased risk of Pro-Pro genotype on cancer susceptibility had been evaluated in TP53 mutation carriers by many studies, but its role in a TP53 negative LFS case study has never been considered.…”

“…309T[G, Chr12 (GRCh37): g.69202580T[G: rs2279744) in the MDM2 promoter regarding an altered tumour susceptibility [16]. MDM2 is the primary negative regulator of TP53 function, which inhibits TP53-mediated transcriptional activity and targets TP53 towards proteasomal degradation [18].…”