Susceptibility and Prevention Recent Natural Selection Identifies a Genetic Variant in a Regulatory Subunit of Protein Phosphatase 2A that Associates with Altered Cancer Risk and Survival

Purpose:A regulated p53-dependent stress response is crucial in suppressing tumor formation and mediating the response to commonly used cancer therapeutics. However, little is known about the human, inherited genetics of this important signaling pathway. Experimental Design: Studies of human genetic variants in the p53 tumor suppressor gene and MDM2 oncogene have shown that single nucleotide polymorphisms (SNP) can affect p53 signaling, confer cancer risk, and alter outcome, and also suggest that the pathway is under evolutionary selective pressure. Here, we attempt to accelerate the identification of functional p53 pathway SNPs by incorporating these characteristics into an analysis of 142 genes that are known to affect p53 signaling. Results: We report that a genomic scan for recent natural selection denotes that of the 142 genes studied, the PPP2R5E gene that encodes a regulatory subunit of the tumor suppressing protein phosphatase 2A resides in a naturally selected genomic region. We go on to show that a selected SNP in PPP2R5E (ε-SNP2) associates with significant allelic differences in the onset (up to 19.2 years; P = 0.0002) and risk (odds ratio, up to 8.1; P = 0.0009) of soft tissue sarcoma development, as well as overall survival (relative risk, up to 3.04; P = 0.026). Conclusions: The PPP2R5E gene is identified as harboring genetic variants that can affect human cancer and are possibly under evolutionary selection pressure. (Clin Cancer Res 2009;15(19):6301–8) The p53 tumor suppressor pathway is central both in reducing cancer frequency in vertebrates and in mediating the response of commonly used cancer therapies (1, 2). Surprisingly, however, very little is known about the inherited genetic variation of this important signaling pathway (3, 4). The p53 pathway is a cellular stress response pathway that is activated upon stresses such as DNA damage and oncogene activation. Once activated, it initiates cellular responses such as DNA repair, cell cycle arrest, cell death (apoptosis), and senescence (5). A growing body of evidence is emerging in the literature that important genes in this pathway could harbor functional single nucleotide polymorphisms (SNP). The SNPs in the p53 pathway that are most frequently studied are found in the p53 and MDM2 genes (p53 codon72; ref. 6, rs1042522, C/G; MDM2 SNP309; ref. 7, rs2279744, T/G). The allelic frequencies for both SNPs vary significantly in different ethnic and racial populations. For example, the G allele of MDM2 SNP309 was found to be at 10% in African Americans (8), 33% in Northern Europeans (9), 45% in Asians (10), and 50% in Ashkenazi Jewish individuals (9). To explain the significant differences for both polymorphisms, allele-specific selective advantages and disadvantages for evolution and/or reproduction have been proposed (8, 11–13). Indeed, two recent reports have provided evidence of recent natural selection for both polymorphic loci (8, 13). For example, in the first report the MDM2 haplotype structure was determined in Caucasians (8). It was noted that the unusually long and frequent haplotype that harbors the G-allele of MDM2 SNP309 deviates significantly from the standard assumptions of selective neutrality using multiple selection tests. These include Authors' Affiliations: Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom; The Institute for Advanced Study, Princeton, New Jersey; The Cancer Institute of New Jersey and UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey; Department of Surgery, Malteser St. Franziskus Hospital, Flensburg, Germany; Department of Oral and Maxillofacial Plastic Surgery, Martin-Luther-University Halle-Wittenberg, Halle, Germany; and German Red Cross Blood Transfusion Service NSTOB, Springe, Germany Received 3/31/09; revised 6/16/09; accepted 6/17/09; published OnlineFirst