A genetic variant in the promoter of CD46 is associated with the risk and prognosis of hepatocellular carcinoma. Issue 11 (1st September 2020)

• Record Type: Journal Article
• Authors: Liu, Fei; Luo, Limei; Liu, Zhongjian; Wu, Sisi; Zhang, Wei; Li, Qin; Peng, Yufu; Wei, Yonggang; Li, Bo
• Is Part Of: Molecular carcinogenesis. Volume 59:Issue 11(2020)
• Page Start: 1243
• Page End: 1255
• Publication Date: 2020-09-01
• Subjects: CD46 -- genetic variation -- hepatocellular carcinoma -- prognosis -- susceptibility; Carcinogenesis -- Molecular aspects -- Periodicals; 616.994071
• DOI: 10.1002/mc.23252
• Languages: English
• ISSNs: 0899-1987

Abstract

Abstract: 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.