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

Abstract

A large body of evidence strongly suggests that the p53 tumor suppressor pathway is central in reducing cancer frequency in vertebrates. The protein product of the haploinsufficient mouse double minute 2 (MDM2) oncogene binds to and inhibits the p53 protein. Recent studies of human genetic variants in p53 and MDM2 have shown that single nucleotide polymorphisms (SNPs) can affect p53 signaling, confer cancer risk, and suggest that the pathway is under evolutionary selective pressure (1-4). In this report, we analyze the haplotype structure of MDM4, a structural homolog of MDM2, in several different human populations. Unusual patterns of linkage disequilibrium (LD) in the haplotype distribution of MDM4 indicate the presence of candidate SNPs that may also modify the efficacy of the p53 pathway. Association studies in 5 different patient populations reveal that these SNPs in MDM4 confer an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively. This report not only implicates MDM4 as a key regulator of tumorigenesis in the human breast and ovary, but also exploits for the first time evolutionary driven linkage disequilibrium as a means to select SNPs of p53 pathway genes that might be clinically relevant.

Fig. 1.

Haplotype structures of the MDM4 oncogene in a Caucasian and in an African American population. (A) A schematic diagram of the MDM4 gene and the SNPs genotyped in the present study. Pairwise linkage disequilibriums are shown for the Caucasian (B), and the African American (C) populations. The upper right triangles report the D′ measures, and the lower left triangles report the r² measures. The inferred haplotype frequencies in the Caucasian (D) and African American (E) populations centered around a particular SNP (SNP-6, rs2369244; denoted with a red box in A), where G(C) is the ancestral (derived) allele.

Fig. 2.

Haplotype structure of the MDM4 oncogene in a Caucasian population of AJ ethnicity. (A) A schematic diagram of the MDM4 gene and the SNPs genotyped in the present study. (B) Pairwise linkage disequilibriums for the Caucasian population of AJ ethnicity. The upper right triangles report the D′ measures, and the lower left triangles report the r² measures. (C) The inferred haplotype frequencies in the population centered on a particular SNP (SNP-9, rs2369244; denoted with a red box in A), where G(C) is the ancestral (derived) allele.

Fig. 3.

A tagSNP that differentiates the nonneutral MDM4-haplotype from the neutral haplotypes demonstrates significant allelic differences in the age of diagnosis of both familial and sporadic ovarian cancer. The cumulative incidence of ovarian cancer for both the women T/T in genotype (black triangles) and C/C in genotype (gray diamonds) for rs1563828 is plotted as a function of age for familial (A) and sporadic (B) disease. The p-values on both panels were calculated by comparing the medians of both genotypes by using a Mann–Whitney Test.