Lack of association between the MDM2-SNP309 polymorphism and breast cancer risk

Background: A T-to-G polymorphism (SNP309) at the promoter region of MDM2 has been recently reported to extend the Sp1 binding site that positively regulates the MDM2 transcription level and consequently, its expression level. MDM2 is the negative regulator of p53 tumor suppressor protein and elevated levels of MDM2 hamper the stress response driven by the p53 pathway. Whether MDM2-SNP309 was associated with breast cancer as a predisposing factor was investigated. Patients and Methods: A case-control study of 223 females diagnosed with breast cancer and 149 female controls sampled from the Turkish population was carried out and the T/G MDM2-SNP309 genotype of participants was determined. Results: There was no significant association of the G/G or G/T genotypes with breast cancer risk (odds ratio (OR) 1.14, 95% confidence interval (CI) 0.59-2.22, and OR 1.20, 95% CI 0.67-2.12, respectively). Stratification of the data for onset age or for menopausal status at the time of diagnosis also revealed no association for either group

Results based on 124 cases of breast cancer and 97 controls from Taiwan suggest that the single nucleotide polymorphism (SNP309) in the MDM2 gene promoter is associated with earlier onset and increased risk of breast cancer

<p>Abstract</p> <p>Background</p> <p>It has been suggested that the single nucleotide polymorphism 309 (SNP309, T -> G) in the promoter region of the MDM2 gene is important for tumor development; however, with regards to breast cancer, inconsistent associations have been reported worldwide. It is speculated that these conflicting results may have arisen due to different patient subgroups and ethnicities studied. For the first time, this study explores the effect of the MDM2 SNP309 genotype on Taiwanese breast cancer patients.</p> <p>Methods</p> <p>Genomic DNA was obtained from the whole blood of 124 breast cancer patients and 97 cancer-free healthy women living in Taiwan. MDM2 SNP309 genotyping was carried out by restriction fragment length polymorphism (RFLP) assay. The multivariate logistic regression and the Kaplan-Meier method were used for analyzing the risk association and significance of age at diagnosis among different MDM2 SNP309 genotypes, respectively.</p> <p>Results</p> <p>Compared to the TT genotype, an increased risk association with breast cancer was apparent for the GG genotype (OR = 3.05, 95% CI = 1.04 to 8.95), and for the TG genotype (OR = 2.12, 95% CI = 0.90 to 5.00) after adjusting for age, cardiovascular disease/diabetes, oral contraceptive usage, and body mass index, which exhibits significant difference between cases and controls. Furthermore, the average ages at diagnosis for breast cancer patients were 53.6, 52 and 47 years for those harboring TT, TG and GG genotypes, respectively. A significant difference in median age of onset for breast cancer between GG and TT+TG genotypes was obtained by the log-rank test (p = 0.0067).</p> <p>Conclusion</p> <p>Findings based on the current sample size suggest that the MDM2 SNP309 GG genotype may be associated with both the risk of breast cancer and an earlier age of onset in Taiwanese women.</p

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

<p>Abstract</p> <p>Background</p> <p>The tumor suppressor gene <it>p53 </it>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 <it>p53 </it>gene is associated with the risk for development of various neoplasms. <it>MDM2 </it>SNP309 is a single nucleotide T to G polymorphism located in the <it>MDM2 </it>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 <it>MDM2 </it>SNP309 and cancer risk. However, the results of the published studies, as well as the subsequent meta-analyses, remain contradictory.</p> <p>Methods</p> <p>To investigate whether currently published epidemiological studies can clarify the potential interaction between <it>MDM2 </it>SNP309 and the functional genetic variant in <it>p53 </it>codon72 (Arg72Pro) and <it>p53 </it>mutation status, we performed a meta-analysis of the risk estimate on 27,813 cases with various tumor types and 30,295 controls.</p> <p>Results</p> <p>The 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 <it>MDM2 </it>SNP309 and tumor susceptibility in the stratified analysis by <it>p53 </it>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 <it>p53 </it>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 <it>p53 </it>mutation status).</p> <p>Conclusions</p> <p>The analyses indicate that <it>MDM2 </it>SNP309 serves as a tumor susceptibility marker, and that there is an association between <it>MDM2 </it>SNP309 and <it>p53 </it>Arg72Pro regarding tumor susceptibility. Further studies that take into consideration environmental stresses and functional genetic variants in the <it>p53</it>-<it>MDM2</it>-related genes are warranted.</p

The ups and downs of p53: understanding protein dynamics in single cells

Cells living in a complex environment must constantly detect, process, and appropriately respond to changing signals. Therefore, all cellular information processing is dynamic in nature. As a consequence, understanding the process of signal transduction often requires detailed quantitative analysis of dynamical behaviors. Here we focus on the oscillatory dynamics of the tumor suppressor protein p53 as a model for studying protein dynamics in single cells to better understand its regulation and function