A functional variant in the RAD51 3' UTR is associated with survival of hepatocellular carcinoma patients.

ABSTRACT

The RAD51 gene plays an important role in DNA repair by homologous recombination, and is involved in the development and progression of multiple cancers. Single nucleotide polymorphisms in RAD51 have been previously described to impact the prognosis of patients with cancers, however, it is still unclear whether this is also true for hepatocellular carcinoma (HCC). This study therefore aimed to identify genetic variants in RAD51 and determine the effect on the survival of patients with HCC. In this study, we performed genotyping assays for RAD51 polymorphisms in a cohort of 368 patients with HCC who had underwent hepatectomy. Using multivariate cox proportional hazards model and Kaplan-Meier analyses with log-rank tests, we compared the survival of patients with HCC according to RAD51 SNP genotypes. We identified one potential functional variant, rs12593359, located in a microRNA (miRNA) binding site in the RAD51 3' untranslated region, to be an independent predictor of overall survival of patients with HCC in the dominant model. Patients carrying GT/TT genotypes had a significantly increased risk of death when compared with those carrying GG genotype (adjusted hazard ratio = 1.34, 95 % confidence interval = 1.02-1.76, P = 0.035). Kaplan-Meier curve analysis showed a markedly shorter survival time for patients with HCC carrying GT/TT genotypes of SNP rs12593359 (19.0 months vs 36.0 months; Plog-rank = 0.012). Notably, this effect was particularly pronounced in several subgroups of patients (e.g., males, Hepatitis B virus-positive patients, patients with a single tumor nodule, patients with alpha-fetoprotein (AFP) < 400 ng/ml, or patients who were cancer embolus-free). Additional expression analysis of quantitative trait loci showed that SNP rs12593359 was significantly associated with RAD51 mRNA expression levels in 483 cell-cultured fibroblasts (P = 1.1 × 10-4). These findings provide evidence that RAD51 rs12593359 is associated with HCC survival and may serve as a promising predictor of survival in patients with HCC.