TY - JOUR
T1 - Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene
AU - Atwal, Gurinder Singh
AU - Kirchhoff, Tomas
AU - Bond, Elisabeth E.
AU - Monagna, Marco
AU - Menin, Chiara
AU - Bertorelle, Roberta
AU - Scaini, Maria Chiara
AU - Bartel, Frank
AU - Böhnke, Anja
AU - Pempe, Christina
AU - Gradhand, Elise
AU - Hauptmann, Steffen
AU - Offit, Kenneth
AU - Levine, Arnold J.
AU - Bond, Gareth L.
PY - 2009/6/23
Y1 - 2009/6/23
N2 - 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.
AB - 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.
KW - Evolutionary selection pressure
KW - Linkage disequilibrium
KW - p53 pathway
KW - Single nucleotide polymorphisms
KW - Tumorigenesis
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U2 - 10.1073/pnas.0901298106
DO - 10.1073/pnas.0901298106
M3 - Article
C2 - 19497887
AN - SCOPUS:67649841887
VL - 106
SP - 10236
EP - 10241
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 25
ER -