MDM4rs4245739 A > C polymorphism correlates with reduced overall cancer risk in a meta-analysis of 69477 subjects

Abstract

Mouse double minute 4 (MDM4) is a p53-interacting oncoprotein that plays an important role in the p53 tumor suppressor pathway. The common rs4245739 A > C polymorphism creates a miR-191 binding site in the MDM4 gene transcript. Numerous studies have investigated the association between this MDM4 polymorphism and cancer risk, but have failed to reach a definitive conclusion. To address this issue, we conducted a meta-analysis by selecting eligible studies from MEDLINE, EMBASE, and Chinese Biomedical databases. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. We also performed genotype-based mRNA expression analysis using data from 270 individuals retrieved from public datasets. A total of 15 studies with 19796 cases and 49681 controls were included in the final meta-analysis. The pooled results revealed that the MDM4 rs4245739C allele is associated with a decreased cancer risk in the heterozygous (AC vs. AA: OR = 0.82, 95% CI = 0.73−0.93), dominant (AC/CC vs. AA: OR = 0.82, 95% CI = 0.72−0.93), and allele contrast models (C vs. A: OR = 0.84, 95% CI = 0.76−0.94). The association was more prominent in Asians and population-based studies. We also found that the rs4245739C allele was associated with decreased MDM4 mRNA expression, especially for Caucasians. Thus the MDM4 rs4245739 A > C polymorphism appears to be associated with decreased cancer risk. These findings would be strengthened by new studies with larger sample sizes and encompassing additional ethnicities.

Association Analysis of TP53 rs1042522, MDM2 rs2279744, rs3730485, MDM4 rs4245739 Variants and Acute Myeloid Leukemia Susceptibility, Risk Stratification Scores, and Clinical Features: An Exploratory Study

“…MDM4 rs4245739 was intensively studied in different types of cancer [ 18 , 22 , 35 , 36 , 43 , 44 , 45 ]. Part of them [ 35 , 36 ] found no association of this variant with cancer susceptibility, while others [ 22 , 43 , 44 , 45 ] found an association with reduced risk of cancer, mainly of breast cancer but not only. The published results are contradictory, depending on the cancer type.…”

<em>MDM2</em> promoter del1518 polymorphism and cancer risk: evidence from 22,931 subjects

“… 1 According to molecular epidemiological researches, genetic polymorphisms have been implicated in diverse carcinogenesis mechanisms. 2 , 3 …”

Associations of MDM2 and MDM4 Polymorphisms with Early-Stage Breast Cancer

“…rs4245739 polymorphism is located in the 3′ untranslated region (UTR) of the MDM4 gene, affects mRNA stability and proteins level [ 31 ]. In this study, we confirmed the impact of MDM4 rs4245739 on ER status, and we consider that AA genotype could indicate better breast cancer prognosis.…”

“…Several studies observed the associations between single nucleotide polymorphisms (SNPs) in MDM2 and MDM4 genes and various cancers [ 9 , 16 , 23 , 24 , 31 , 32 , 33 , 34 , 35 , 36 ]. In spite of this, the influence on breast cancer has not been sufficiently investigated yet.…”