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 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.
Atwal
Gurinder Singh
GS
The Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom.
Kirchhoff
Tomas
T
Bond
Elisabeth E
EE
Montagna
Marco
M
Monagna
Marco
M
Menin
Chiara
C
Bertorelle
Roberta
R
Scaini
Maria Chiara
MC
Bartel
Frank
F
Böhnke
Anja
A
Pempe
Christina
C
Gradhand
Elise
E
Hauptmann
Steffen
S
Offit
Kenneth
K
Levine
Arnold J
AJ
Bond
Gareth L
GL
D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D006239:Haplotypes; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012641:Selection, Genetic
D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins