MDM2 promoter SNP344T>A (rs1196333) status does not affect cancer risk

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.

Figure 1. MDM2 promoter P2.

(A) The promoter is located between exon 1 and 2 of the MDM2 gene and harbours SNP285 (rs117039649), SNP309 (rs2279744) and SNP344 (1196333). (B) Representative sequencing chromatogram from an individual heterozygous for SNP344 (sequence showed as reverse complementary to the sense strand).

Figure 2. SNP344 and mdm2 expression.

Box-plots representing log transformed relative levels of total MDM2 mRNA (A) and promoter P2 specific mRNA (B) in individuals harbouring the SNP344TT genotype versus the TA and AA genotypes.

Figure 3. Impact of SNP344A on cancer risk.

Forrest plot showing the effect of SNP344A on risk of ovarian, breast, endometrial and prostatic cancer, as compared to healthy controls, among individuals harbouring the SNP309TG genotype (A), the SNP309TT genotype (B) and the TG and TT genotypes combined (C).