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

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-06, Vol.106 (25), p.10236-10241
Main Authors: Atwal, Gurinder Singh, Kirchhoff, Tomas, Bond, Elisabeth E, Monagna, Marco, Menin, Chiara, Bertorelle, Roberta, Scaini, Maria Chiara, Bartel, Frank, Böhnke, Anja, Pempe, Christina, Gradhand, Elise, Hauptmann, Steffen, Offit, Kenneth, Levine, Arnold J, Bond, Gareth L
Format: Article
Language:English
Subjects:
African Americans
Biological Sciences
Breast cancer
Breast Neoplasms - genetics
Cancer
Cell Transformation, Neoplastic - genetics
Datasets
Evolution
Evolution, Molecular
Female
Genes
Genetic diversity
Genetics
Haplotypes
Human genetics
Humans
Nuclear Proteins - genetics
Oncogenes
Ovarian cancer
Ovarian Neoplasms - genetics
Pedigree
Polymorphism
Polymorphism, Single Nucleotide
Proteins
Proto-Oncogene Proteins - genetics
Selection, Genetic
Tumors
White people
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0901298106