A genetic variant in the promoter of CD46 is associated with the risk and prognosis of hepatocellular carcinoma

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.

“Complimenting the Complement”: Mechanistic Insights and Opportunities for Therapeutics in Hepatocellular Carcinoma

“…More importantly, the CD46 SNP rs2796267 was recently found to contribute to susceptibility and disease outcomes in HCC by modifying promoter activity. The rs2796267 AG/GG genotype was found to be associated with worse prognosis of resected patients with HCC ( 331 ). Table 2 summarizes the various SNPs found in complement proteins relevant to the pathogenesis of HCC.…”

Genetic variants in NER pathway genes predict hepatitis B virus-related hepatocellular carcinoma survival

“…It has been well known that single nucleotide polymorphisms (SNPs), an important form of genetic variants, may play an important role in prognosis of cancers including HCC [6][7][8] . Increasing evidence indicates that SNPs may affect the outcome of the patients with HCC, which have been used as biomarkers for predicting outcome of the patients with HCC [9,10] . However, previous genome-wide association study (GWAS) focused mainly on the SNPs with the strict P values of 5×10 − 8 , the vast majority of the identi ed top SNPs lack functional annotations [11] .…”