Qu Shimian, Long Jirong, Cai Qiuyin, Shu Xiao-Ou, Cai Hui, Gao Yu-Tang, Zheng Wei
Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Clin Cancer Res. 2008 Aug 1;14(15):4787-93. doi: 10.1158/1078-0432.CCR-08-0083.
Ample evidence supports an important role of tumor metastasis suppressor genes in cancer metastatic processes. We evaluated the association of genetic polymorphisms of metastasis suppressor gene NME1 with breast cancer prognosis in a follow-up study of patients with primary breast cancer and further investigated the functions of these polymorphisms.
NME1 genotypes were analyzed in a cohort of 1,134 breast cancer patients recruited as part of the Shanghai Breast Cancer Study who were followed for a median of 7.1 years. In vitro biochemical analyses were carried out to examine the function of NME1 gene polymorphisms.
Single nucleotide polymorphisms (SNP) in the promoter region of the NME1 gene were found to be associated with breast cancer prognosis. Patients carrying the C allele in rs16949649 were associated with higher breast cancer-specific mortality [hazard ratio (HR), 1.4; 95% confidence interval (95% CI), 1.1-1.9] compared with those carrying the wild-type allele, and the association was more evident in patients with an early-stage cancer (HR, 1.7; 95% CI, 1.2-2.5). SNP rs2302254 was also associated with breast cancer prognosis, and the association was statistically significant for the risk of breast cancer relapse, metastasis, and death (HR, 1.3; 95% CI, 1.0-1.6). In vitro biochemical analyses showed that minor alleles in rs2302254 and rs3760468, which is in strong linkage disequilibrium with rs16949646, altered nuclear proteins binding capacity and reduced NME1 promoter activity, supporting the results from an association study of these SNPs with breast cancer survival.
Promoter polymorphisms in the NME1 gene may alter its expression and influence breast cancer survival.
大量证据支持肿瘤转移抑制基因在癌症转移过程中发挥重要作用。在一项对原发性乳腺癌患者的随访研究中，我们评估了转移抑制基因NME1的基因多态性与乳腺癌预后的关联，并进一步研究了这些多态性的功能。
在作为上海乳腺癌研究一部分招募的1134例乳腺癌患者队列中分析NME1基因型，这些患者的中位随访时间为7.1年。进行体外生化分析以检查NME1基因多态性的功能。
发现NME1基因启动子区域的单核苷酸多态性（SNP）与乳腺癌预后相关。与携带野生型等位基因的患者相比，在rs16949649中携带C等位基因的患者乳腺癌特异性死亡率更高[风险比（HR），1.4；95%置信区间（95%CI），1.1-1.9]，并且这种关联在早期癌症患者中更明显（HR，1.7；95%CI，1.2-2.5）。SNP rs2302254也与乳腺癌预后相关，并且对于乳腺癌复发、转移和死亡风险具有统计学意义（HR，1.3；95%CI，1.0-1.6）。体外生化分析表明，rs2302254和与rs16949646处于强连锁不平衡的rs3760468中的次要等位基因改变了核蛋白结合能力并降低了NME1启动子活性，支持了这些SNP与乳腺癌生存关联研究的结果。
NME1基因的启动子多态性可能改变其表达并影响乳腺癌生存。
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