Genetic Variants in p53 Pathway Genes Affect Survival of Patients with HBV-Related Hepatocellular Carcinoma.

PURPOSE

is a suppressor gene closely related to carcinogenesis. However, the associations between genetic variants in the p53 signaling pathway and prognosis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain unknown. The current study aims to analyze associations between the single nucleotide polymorphisms (SNPs) in p53 pathway-related genes and survival of patients with HBV-HCC.

METHODS

We evaluated the associations between 4698 SNPs in 70 genes of the p53 pathway and overall survival (OS) of 866 patients in additive genetic models by using Cox proportional hazards regression analysis. Stepwise multivariable Cox regression analysis was conducted to determine the independent effects of identified SNPs in single-locus analyses. The expression of quantitative trait loci (eQTL) was also analyzed using data from GTEx and 1000 Genomes Project, and functional prediction of SNPs was performed by using RegulomeDB v2.2, 3DSNP v2.0, HaploReg v4.2 and VannoPortal.

RESULTS

We found that two novel SNPs of rs7925603 A > G and rs4396625 A > T, were significantly and independently associated with OS [adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were 1.27 (1.10-1.48) and 0.77 (0.66-0.91), respectively; = 0.001 and = 0.002, respectively] and that the combined risk genotypes of these SNPs showed a significant association with OS in patients with HBV-HCC ( < 0.001). Further eQTL analysis in the GTEx dataset showed that the rs7925603 G allele was associated with lower mRNA expression levels, while the rs4396625 T allele was associated with higher mRNA expression levels in whole blood cells.

CONCLUSION

We identified two observed survival-associated SNPs in and in the p53 pathway, which influenced HBV-HCC survival possibly through a mechanism of altering mRNA expression. Large studies are warranted to validate our findings.