Genetic variants of cell cycle pathway genes predict disease‐free survival of hepatocellular carcinoma

Disruption of the cell cycle pathway has previously been related to development of human cancers. However, associations between genetic variants of cell cycle pathway genes and prognosis of hepatocellular carcinoma ( HCC ) remain largely unknown. In this study, we evaluated the associations between 24 potential functional single nucleotide polymorphisms (SNPs) of 16 main cell cycle pathway genes and disease‐free survival ( DFS ) of 271 HCC patients who had undergone radical surgery resection. We identified two SNP s, i.e., SMAD 3 rs11556090 A>G and RBL 2 rs3929G>C, that were independently predictive of DFS in an additive genetic model with false‐positive report probability ( FPRP ) <0.2. The SMAD 3 rs11556090G allele was associated with a poorer DFS , compared with the A allele [hazard ratio ( HR ) = 1.46, 95% confidential interval (95% CI ) = 1.13–1.89, P  =   0.004]; while the RBL 2 rs3929 C allele was associated with a superior DFS , compared with the G allele ( HR  = 0.74, 95% CI  = 0.57–0.96, P  = 0.023). Additionally, patients with an increasing number of unfavorable genotypes ( NUG s) of these loci had a significant shorter DFS ( P trend  = 0.0001). Further analysis using receiver operating characteristic ( ROC ) curves showed that the model including the NUG s and known prognostic clinical variables demonstrated a significant improvement in predicting the 1‐year DFS ( P  =   0.011). Moreover, the RBL 2 rs3929 C allele was significantly associated with increased mRNA expression levels of RBL 2 in liver tissue ( P  =   1.8 × 10 −7 ) and the whole blood ( P  =   3.9 × 10 −14 ). Our data demonstrated an independent or a joint effect of SMAD 3 rs11556090 and RBL 2 rs3929 in the cell cycle pathway on DFS of HCC , which need to be validated by large cohort and biological studies.