MDM2 promoter SNP344T>A (rs1196333) status does not affect cancer risk.
MDM2 promoter SNP344T>A (rs1196333) status does not affect cancer risk.
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DOI：
10.1371/journal.pone.0036263
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lønning PE
中科院分区：
文献类型：
--
作者：
Knappskog S;Gansmo LB;Romundstad P;Bjørnslett M;Trovik J;Sommerfelt-Pettersen J;Løkkevik E;Norwegian Breast Cancer Group trial NBCG VI;Tollenaar RA;Seynaeve C;Devilee P;Salvesen HB;Dørum A;Hveem K;Vatten L;Lønning PE
MDM2原癌基因在生长控制和细胞凋亡等中枢细胞过程中起着关键作用，该基因在肉瘤中经常被扩增。位于MDM2启动子P2的两个多态已被证明影响癌症风险。这些多态之一(SNP309T>；G；rs2279744)促进Sp1转录因子与启动子结合，并与癌症风险增加相关。相反，位于rs2279744上游24bp的SNP285G>；C(Rs117039649)与SNP309G等位基因完全连锁不平衡，减少了Sp1的募集，降低了癌症风险。因此，MDM2表达的微调已被证明在肿瘤发生中具有重要意义。我们评估了位于SNP309T等位基因上的第三个MDM2启动子P2多态(SNP344T>；A；rs1196333)的潜在功能效应。而在计算机分析中发现SNP344A调节TFAP2A、SPIB和AP1转录因子的结合，我们发现SNP344状态对MDM2的表达水平没有影响。评估SNP344A在健康高加索人(n = 2,954)和卵巢癌(n = 1,927)、乳腺癌(n = 1,271)、子宫内膜癌(n = 895)和前列腺癌(n = 641)患者中的频率，我们发现这些癌症形式中的任何一种与健康对照组(分别为6.1%和4.9%，5.0%，5.4%和7.2%)的SNP344A分布没有显著差异。总之，我们的发现没有证据表明SNP344A可能影响MDM2转录或癌症风险。
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.
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Lønning PE