The MDM2 protein is an ubiquitin ligase that plays a critical role in regulating the levels and activity of the p53 protein, which is a central tumor suppressor. A SNP in the human MDM2 gene (SNP309 T/G) occurs at frequencies dependent on demographic history and has been shown to have important differential effects on the activity of the MDM2 and p53 proteins and to associate with altered risk for the development of several cancers. In this report, the haplotype structure of the MDM2 gene is determined by using 14 different SNPs across the gene from three different population samples: Caucasians, African Americans, and the Ashkenazi Jewish ethnic group. The results presented in this report indicate that there is a substantially reduced variability of the deleterious SNP309 G allele haplotype in all three populations studied, whereas multiple common T allele haplotypes were found in all three populations. This observation, coupled with the relatively high frequency of the G allele haplotype in both and Caucasian and Ashkenazi Jewish population data sets, suggests that this haplotype could have undergone a recent positive selection sweep. An entropy-based selection test is presented that explicitly takes into account the correlations between different SNPs, and the analysis of MDM2 reveals a significant departure from the standard assumptions of selective neutrality.cancer ͉ p53 ͉ population genetics ͉ SNP ͉ entropy I n response to a wide variety of stresses, such as DNA damage or oncogene activation, the p53 tumor suppressor protein is activated and initiates a transcriptional program leading to cell cycle arrest, cell senescence or apoptosis (1). This eliminates clones of cells that have acquired mutations, which arise at a high frequency when DNA replication or the cell cycle proceeds under stress. When the p53 gene is mutated in either the germ line or in a somatic cell, many types of cancers can arise (2). The p53 protein is regulated by a ubiquitin ligase, the MDM2 protein, which binds to p53, blocking its function as a transcription factor, and polyubiquitinates the p53 protein sending it to the proteiosome for degradation (3). The MDM2 gene in turn is positively regulated by p53-mediated transcription, setting up an autoregulatory loop that keeps both proteins at moderate levels. Stress responses perturb this feedback loop, which leads to the initiation of p53-dependent apoptosis.Functional SNPs in the human genome have been identified in both the p53 and the MDM2 genes (4). In the p53 gene, a SNP (codon 72) results in the change of a proline residue to an arginine at codon 72 of the p53 protein (p53-Pro and p53-Arg, respectively). Multiple groups have shown that p53-Pro is weaker than p53-Arg in its ability to both suppress cellular transformation and induce apoptosis in cell culture (5-8), and can associate with an earlier onset of tumor formation and a poorer tumor response to chemotherapy in humans (7, 9, 10). In the MDM2 gene, a SNP (SNP309) results in a nucleotide change from the wild-type thymine (T...

Major gene rearrangements involving BRCA1 BRCA2 contribute little to the burden of inherited predisposition of breast cancer in Ashkenazi Jews.

Objective The objective of this feasibility study was to assess the number of patients that could be included in a future Real World Evidence study, which would be designed to explore the impact of Paxlovid (nirmatrelvir/ritonavir) on patient outcomes and healthcare resource utilization (HCRU). We also intend to assess the comparability of the patients who were treated with Paxlovid versus patients who did not receive the treatment, either because they declined any COVID-19 treatment or were diagnosed with COVID-19 prior to Paxlovid availability. Methods This retrospective observational secondary data study used data from the Maccabi Healthcare Services database during the identification period of June 1, 2021, to February 28, 2022. The study population included patients with at least one positive SARS-CoV-2 RT-PCR test, or a formal rapid antigen test for SARS-CoV-2, during the identification period, the date of which also served as the COVID-19 diagnosis date. We then divided the study population into the following cohorts: Pre-Paxlovid Time Period and Paxlovid Time Period, which was further split into Paxlovid Treated and Paxlovid Untreated. Results Application of inclusion and exclusion criteria to the study population rendered 20,284 patients in the Pre-Paxlovid Time Period cohort and 5,542 in the Paxlovid Time Period cohort that were eligible to receive Paxlovid. This resulted in 3,714 in the Paxlovid Treated and 1,810 in the Paxlovid Untreated cohorts. Conclusions This RWE feasibility study of patients with a positive test for COVID-19 between June 1, 2021 to February 28, 2022 illustrates potential comparability between cohorts, as described by their demographics and characteristics.