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

Abstract

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 SNPs, i.e., SMAD3 rs11556090 A>G and RBL2 rs3929G>C, that were independently predictive of DFS in an additive genetic model with false-positive report probability (FPRP) <0.2. The SMAD3 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 RBL2 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 (NUGs) 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 NUGs and known prognostic clinical variables demonstrated a significant improvement in predicting the 1-year DFS (P = 0.011). Moreover, the RBL2 rs3929 C allele was significantly associated with increased mRNA expression levels of RBL2 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 SMAD3 rs11556090 and RBL2 rs3929 in the cell cycle pathway on DFS of HCC, which need to be validated by large cohort and biological studies.

Keywords: Cell cycle pathway; hepatocellular carcinoma; single-nucleotide polymorphism; survival.

Figure 1

SMAD3 rs11556090 and RBL2 rs3929 associated with disease‐free survival of hepatocellular carcinoma patients. (A–D) Kaplan–Meier survival curves of single nucleotide polymorphisms in different genetic models: rs11556090 in an additive genetic model (A) and dominant model (B); rs3929 in an additive genetic model (C) and recessive model (D). (E) Kaplan–Meier survival curves of combined effects of the unfavorable genotypes. (F) Receiver operating characteristic (ROC) curve and area under the curve (AUC) estimation for prediction of 1‐year DFS.

Figure 2

In silico functional validation of SMAD3 rs11556090 and RBL2 rs3929. Location‐map of rs11556090 (A) and rs3929 (B) in UCSC website (https://genome.ucsc.edu/); The expression quantitative trait loci analysis (eQTL) from the GTEx Portal (http://www.gtexportal.org/home/) for RBL2 rs3929 in liver tissue (C) and the whole blood (D); eQTL analysis by using Asian population of HapMap3 data for rs11556090 (E) and rs3929 (F).