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

   


Authors: Atwal, G. S.; Kirchhoff, T.; Bond, E. E.; Monagna, 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.
Article Title: 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.
Keywords: controlled study; single nucleotide polymorphism; polymorphism, single nucleotide; proto-oncogene proteins; cancer risk; ovarian neoplasms; genetic variability; haplotypes; linkage disequilibrium; breast neoplasms; protein p53; carcinogenesis; evolutionary selection pressure; p53 pathway; single nucleotide polymorphisms; tumorigenesis; protein mdmx; haplotype; cell transformation, neoplastic; evolution, molecular; nuclear proteins; oncogenes; pedigree; selection (genetics); vertebrata
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 106
Issue: 25
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2009-06-23
Start Page: 10236
End Page: 10241
Language: English
DOI: 10.1073/pnas.0901298106
PUBMED: 19497887
PROVIDER: scopus
PMCID: PMC2700939
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-67649841887&partnerID=40&md5=e919db5440ca984c4b856eb8a5288e84
Notes: --- - "Cited By (since 1996): 6" - "Export Date: 30 November 2010" - "CODEN: PNASA" - "Source: Scopus"
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MSK Authors
  1. Kenneth Offit
    788 Offit
  2. Tomas Kirchhoff
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