Haplotype structure and selection of the MDM2 oncogene in humans

Abstract

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...

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

“…The above-described analysis suggests that the genetic variants in the MDM4 oncogene have undergone a selective sweep. As this scenario is similar to the haplotype containing the functional SNP309 in the MDM2 oncogene (33), it was hypothesized that the MDM4 haplotype distribution might also harbor one or more functional SNPs and therefore also demonstrate allelic differences in human cancer populations. To test this hypothesis, a set of SNPs was used, each of which can differentiate the nonneutral major MDM4-haplotype (the major alleles) from the other neutral MDM4 haplotypes, and it was determined whether their genotypes were associated with either altered cancer risk in case/control studies for familial and sporadic breast cancer or age-dependent incidence in case studies for both familial and sporadic ovarian cancers.…”

“…However, these tests suffer from 3 main deficits: (i) they ignore multiallelic correlations and thereby reduce their power to detect a recent reduction in haplotype diversity, i.e., selective sweep; (ii) historical episodes of reduced population sizes (population bottlenecks) can give rise to a distribution of allele frequencies that appear to be nonneutral; and (iii) these classical tests do not explicitly pinpoint which allele or haplotype is under selection pressure. In an attempt to overcome these deficits, we also performed a previously described selection test for each SNP, based on the entropy of the marginal haplotype distributions (33). Interestingly, the entropy-haplotype selection tests and the majority of the classical selection tests suggest a significant departure from neutrality of the MDM4 oncogene in the Caucasian, African American, and Ashkenazi-Jewish populations (Table 1).…”

“…As mentioned in the introduction, it was previously shown that the nonneutral haplotype of the MDM2 oncogene harbors the G-allele of MDM2 SNP309 and associates with an attenuation of the p53 pathway, altered MDM2 expression, and enhanced early onset of, or increased risk for, tumorigenesis (33). In this report, we demonstrate that in the case of the MDM4 oncogene, it is the neutral haplotype that associates with increased breast cancer risk and an earlier age of onset of ovarian cancer, which could suggest a weaker p53 pathway.…”

“…These observations suggested that the human p53 pathway could be acted on by an evolutionary selection pressure. Indeed, it had been previously and subsequently shown that a well-regulated p53 pathway is crucial for proper murine embryonic development, embryonic implantation, pregnancy rates, and litter sizes (33,34), and also human embryonic implantation (35). Thus, the p53 pathway not only plays a role in genomic error correction in the lifetime of humans, but also determines the fate of viable genetic transmission on the timescale of generations.…”

“…Recently, the MDM2 haplotype structure was determined in humans from several different demographic groups (33). It was noted that the frequency of the haplotype harboring the functional G-allele of MDM2 SNP309 deviated significantly from the standard assumptions of models of selective neutrality by using multiple selection tests, including an entropy-based selection test that compares both the frequency and long-range correlations of an allele with a simulated neutral model, where the allele is selectively neutral.…”