Abstract
The MDM2 proto-oncogene plays a key role in central cellular processes like growth control and apoptosis, and the gene locus is frequently amplified in sarcomas. Two polymorphisms located in the MDM2 promoter P2 have been shown to affect cancer risk. One of these polymorphisms (SNP309T>G; rs2279744) facilitates Sp1 transcription factor binding to the promoter and is associated with increased cancer risk. In contrast, SNP285G>C (rs117039649), located 24 bp upstream of rs2279744, and in complete linkage disequilibrium with the SNP309G allele, reduces Sp1 recruitment and lowers cancer risk. Thus, fine tuning of MDM2 expression has proven to be of significant importance with respect to tumorigenesis. We assessed the potential functional effects of a third MDM2 promoter P2 polymorphism (SNP344T>A; rs1196333) located on the SNP309T allele. While in silico analyses indicated SNP344A to modulate TFAP2A, SPIB and AP1 transcription factor binding, we found no effect of SNP344 status on MDM2 expression levels. Assessing the frequency of SNP344A in healthy Caucasians (n = 2,954) and patients suffering from ovarian (n = 1,927), breast (n = 1,271), endometrial (n = 895) or prostatic cancer (n = 641), we detected no significant difference in the distribution of this polymorphism between any of these cancer forms and healthy controls (6.1% in healthy controls, and 4.9%, 5.0%, 5.4% and 7.2% in the cancer groups, respectively). In conclusion, our findings provide no evidence indicating that SNP344A may affect MDM2 transcription or cancer risk.
Highlights
The Mouse Double Minute 2 homolog (MDM2) is a key regulator of p53 as well as retinoblastoma protein function [1,2,3]
While subsequent studies have confirmed an association between SNP309G and the risk of multiple cancer forms, the effect of this SNP seems to differ between ethnic groups: while most studies performed in Asian or Ashkenazi Jewish populations reports the SNP309G variant to enhance cancer risk many studies conducted in Caucasian populations have failed to reproduce a similar effect [11,12]
MDM2 controls processes like growth arrest, apoptosis and senescence, and MDM2 gene amplification and enhanced translation have been observed in many tumour forms [2,4,5,6,7]
Summary
The Mouse Double Minute 2 homolog (MDM2) is a key regulator of p53 as well as retinoblastoma protein function [1,2,3]. Elevated MDM2 protein levels due to MDM2 gene amplification or other mechanisms have been regarded as an alternative to TP53 mutations diminishing p53 function in many human cancers [2,4,5,6,7]. SNP309G enhances MDM2 expression levels by increasing Sp1 transcription factor binding and was subsequently shown to be associated with increased risk and an early age at diagnosis of several malignancies [8,9,10]. While subsequent studies have confirmed an association between SNP309G and the risk of multiple cancer forms, the effect of this SNP seems to differ between ethnic groups: while most studies performed in Asian or Ashkenazi Jewish populations reports the SNP309G variant to enhance cancer risk many studies conducted in Caucasian populations have failed to reproduce a similar effect [11,12]
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