Department of Liver Surgery, Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Clinical Immunological Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Mol Carcinog. 2020 Nov;59(11):1243-1255. doi: 10.1002/mc.23252. Epub 2020 Sep 1.
CD46 (also known as membrane cofactor protein), which is a member of the membrane-bound complement regulatory protein family, has been reported to cause cancer cells to escape complement-dependent cytotoxicity. However, the association between CD46 polymorphisms and the risk of hepatocellular carcinoma (HCC) has not been investigated. This two-stage association study was conducted to assess the relationship between the tagging single nucleotide polymorphisms (tagSNPs) of CD46 and HCC risk and prognosis. A series of functional analyses were performed to study the underlying mechanisms. Among the eight tagSNPs, rs2796267 (P = .003) and rs2796268 (P = .011) were found to modify HCC risk in the discovery set. Only rs2796267 (P < .0001) was confirmed to be associated with HCC susceptibility in the validation set. Compared with the wild-type AA genotype, the GG genotype significantly increased the HCC risk (adjusted odds ratio [OR] = 2.03; 95% confidence interval [CI], 1.34-3.08; P = .001). Moreover, subgroups analysis suggested a positive correlation among male and younger patients, especially among drinkers, smokers, and hepatitis B surface antigen-positive individuals. In functional analyses, we found that the rs2796267 G allele in the promoter region of CD46 could increase the expression of CD46 by affecting the binding affinity of STAT5a. Furthermore, Cox regression analysis revealed that the rs2796267 AG/GG genotype was significantly associated with worse prognosis of resected patients with HCC (hazard ratio = 2.27; 95% CI, 1.27-4.05; P = .006). These results suggest that the CD46 rs2796267 polymorphism may contribute to susceptibility and prognosis of HCC by altering promoter activity.
CD46（也称为膜辅因子蛋白）是膜结合补体调控蛋白家族的成员，据报道，它可使癌细胞逃避补体依赖性细胞毒性。然而，CD46 多态性与肝细胞癌（HCC）风险之间的关联尚未得到研究。本研究进行了两阶段的关联研究，以评估 CD46 标记单核苷酸多态性（tagSNP）与 HCC 风险和预后的关系。进行了一系列功能分析以研究潜在的机制。在这 8 个 tagSNP 中，rs2796267（P = .003）和 rs2796268（P = .011）在发现集中被发现可修饰 HCC 风险。仅 rs2796267（P < .0001）在验证集中被证实与 HCC 易感性相关。与野生型 AA 基因型相比，GG 基因型显著增加 HCC 风险（校正后的优势比[OR] = 2.03；95%置信区间[CI]，1.34-3.08；P = .001）。此外，亚组分析表明，rs2796267 位于 CD46 启动子区域的 G 等位基因可能通过影响 STAT5a 的结合亲和力来增加 CD46 的表达，从而与男性和年轻患者，尤其是饮酒者、吸烟者和乙型肝炎表面抗原阳性者之间存在正相关。在功能分析中，我们发现 CD46 启动子区域的 rs2796267G 等位基因可能通过影响 STAT5a 的结合亲和力来增加 CD46 的表达，从而与男性和年轻患者，尤其是饮酒者、吸烟者和乙型肝炎表面抗原阳性者之间存在正相关。在功能分析中，我们发现 CD46 启动子区域的 rs2796267G 等位基因可能通过影响 STAT5a 的结合亲和力来增加 CD46 的表达，从而与男性和年轻患者，尤其是饮酒者、吸烟者和乙型肝炎表面抗原阳性者之间存在正相关。在功能分析中，我们发现 CD46 启动子区域的 rs2796267G 等位基因可能通过影响 STAT5a 的结合亲和力来增加 CD46 的表达，从而与男性和年轻患者，尤其是饮酒者、吸烟者和乙型肝炎表面抗原阳性者之间存在正相关。在功能分析中，我们发现 CD46 启动子区域的 rs2796267G 等位基因可以增加 CD46 的表达，这可能是通过影响 STAT5a 的结合亲和力来实现的。此外，cox 回归分析显示 rs2796267 AG/GG 基因型与 HCC 患者（危险比 = 2.27；95% CI，1.27-4.05；P = .006）的预后显著相关。这些结果表明，CD46 rs2796267 多态性可能通过改变启动子活性而导致 HCC 的易感性和预后。
