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

Atwal, G. S., Kirchhoff, T., Bond, E. E., Montagna, M., Menin, C., Bertorelle, R., Scaini, M. C., Bartel, F., Böhnke, A., Pempe, C., Gradhand, E., Hauptmann, S., Offit, K., Levine, A. J., Bond, G. L. (2009) Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene. Proc Natl Acad Sci U S A, 106 (25). pp. 10236-10241. ISSN 1091-6490 (Electronic)0027-8424 (Linking)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/19497887
DOI: 10.1073/pnas.0901298106

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.

Item Type: Paper
Uncontrolled Keywords: Breast Neoplasms/ genetics Cell Transformation, Neoplastic/ genetics Evolution, Molecular Female Haplotypes Humans Nuclear Proteins/ genetics Oncogenes Ovarian Neoplasms/ genetics Pedigree Polymorphism, Single Nucleotide Proto-Oncogene Proteins/ genetics Selection, Genetic
Subjects: bioinformatics
diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
CSHL Authors:
Communities: CSHL labs > Atwal lab
Depositing User: Matt Covey
Date Deposited: 21 Feb 2013 21:22
Last Modified: 08 Nov 2017 20:46
PMCID: PMC2700939
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27332

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