A functional SNP in the MDM2 promoter, pigmentary phenotypes, and risk of skin cancer.
A functional SNP in the MDM2 promoter, pigmentary phenotypes, and risk of skin cancer.
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DOI：
10.1007/s10552-008-9231-9
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发表时间：
2009-03
影响因子：
2.3
通讯作者：
Han, Jiali
中科院分区：
文献类型：
--
作者：
Nan, Hongmei;Qureshi, Abrar A.;Hunter, David J.;Han, Jiali
MDM 2癌蛋白是肿瘤抑制因子p53的关键负调节因子。启动子区的功能性MDM 2单核苷酸多态性（SNP 309）增加了转录激活因子Sp1对MDM 2基因启动子的亲和力，导致MDM 2的更高表达，从而抑制p53转录活性。紫外线诱导的p53激活促进皮肤瞬时色素沉着，常见的p53 Arg 72 Pro多态性改变蛋白质的转录活性。我们在护士健康研究（NHS）的一项巢式病例对照研究中评估了MDM 2 SNP 309及其与p53 Arg 72 Pro多态性的相互作用对色素表型和皮肤癌风险的影响，该研究包括219例黑色素瘤病例、286例鳞状细胞癌（SCC）病例、300例基底细胞癌（BCC）病例和873例对照，以及其他研究的对照。我们发现MDM 2 SNP 309的G等位基因与3207名女性手臂上痣的存在/不存在呈负相关，这些女性来自NHS内三项巢式病例对照研究的对照组。与MDM 2 SNP 309 T/T基因型相比，T/G和G/G基因型手臂上有痣的调整后比值比（OR）分别为0.92（95%置信区间（CI），0.78-1.08）和0.68（95%CI，0.53-0.87），（P，趋势，0.005）。我们观察到提示性证据表明，携带MDM 2 SNP 309 G等位基因与儿童晒黑倾向之间存在关联（校正OR，1.30; 95%CI，1.01-1.68）。MDM 2 SNP 309与三种皮肤癌中的任何一种都没有显着关联。对于SCC，三种MDM 2基因型的风险增加趋势在p53 Pro携带者（p，趋势，0.05）中比p53 Arg/Arg野生型组（p，趋势，0.99; p，交互作用，0.07）更强。这些结果为MDM 2 SNP 309可能参与猪的性状提供了证据。
The MDM2 oncoprotein is a key negative regulator of the tumor suppressor p53. A functional MDM2 single nucleotide polymorphism (SNP309) in the promoter region increases the affinity of transcription activator Sp1 for the MDM2 gene promoter, resulting in higher expression of MDM2 and thus inhibition of p53 transcriptional activity. UV-induced p53 activation promotes cutaneous transient pigmentation, and the common p53 Arg72Pro polymorphism alters the protein’s transcriptional activity. We evaluated the effect of the MDM2 SNP309 and its interaction with the p53 Arg72Pro polymorphism on pigmentary phenotypes and skin cancer risk in a nested case-control study within the Nurses’ Health Study (NHS) among 219 melanoma cases, 286 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 873 controls, and among controls from other studies. We found that the G allele of the MDM2 SNP309 was inversely associated with the presence/absence of moles on the arm among 3207 women pooled from controls of three nested case-control studies within the NHS. Compared with the MDM2 SNP309 T/T genotype, adjusted odds ratios (ORs) of having moles on the arms for T/G and G/G genotypes were 0.92 (95% confidence interval (CI), 0.78–1.08) and 0.68 (95%CI, 0.53–0.87), respectively (P, trend, 0.005). We observed suggestive evidence of the association between the carriage of the MDM2 SNP309 G allele and childhood tanning tendency (adjusted OR, 1.30; 95% CI, 1.01–1.68). No significant associations were found between the MDM2 SNP309 and any of the three types of skin cancer. For SCC, the trend of increased risk across the three genotypes of MDM2 was stronger among p53 Pro carriers (p, trend, 0.05) than p53 Arg/Arg wildtype group (p, trend, 0.99; p, interaction, 0.07). These results provide evidence for the potential involvement of MDM2 SNP309 in pigmentary traits.
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