Oncotarget

Research Perspectives:

MDM2 promoter SNP285 and SNP309; phylogeny and impact on cancer risk

Stian Knappskog _ and Per E. Lønning

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Oncotarget. 2011; 2:251-258. https://doi.org/10.18632/oncotarget.243

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Abstract

Stian Knappskog1,2 and Per E. Lønning1,2

1Section of Oncology, Institute of Medicine, University of Bergen, 5020 Bergen, Norway

2Department of Oncology, Haukeland University Hospital, 5021 Bergen, Norway

Received: March 22, 2011; Accepted: March 23, 2011; Published: March 23, 2011;

Keywords: MDM2, p53, polymorphism, breast cancer, ovarian cancer, evolutionary selection

Correspondence:

Stian Knappskog, e-mail:

Abstract

MDM2 plays a key role to physiological processes like growth arrest, senescence and apoptosis. It binds to and inhibits key proteins like p53 and the RB protein, and MDM2 amplification as well as protein overexpression without amplification is seen in many solid tumors. An MDM2 promoter polymorphism (SNP309T>G) has been found associated with enhanced Sp1 transcription factor binding and elevated MDM2 transcription. While 309G has been found associated with elevated cancer risk and young age at diagnosis of different cancers, results in Caucasians have been at variance. Recently, we reported a second polymorphism (SNP285G>C) located on the 309G allele. The 285C/309G haplotype accounts for about 12% of all 309G alleles among Norwegians, Dutch and British habitants. Assessing Sp1 binding to the MDM2 promoter using surface plasmon resonance technology, we found SNP309G to enhance Sp1 binding by 22% while SNP285C reduced Sp1 binding by 51%. SNP285C reduced the risk of breast cancer and ovarian cancer among 309TG/309GG carriers by 21 and 26%, respectively, but in particular the risk of ovarian cancer among 309TG heterozygotes (reduction by 37%). The fact that the 285C/309G haplotype accounted for only 1.9% of all 309G alleles among Finns and was absent in Chinese indicate 285C to be a young polymorphism.


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