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

Shun Liu,Tian‐Bo Yang,Dong‐Xiang Pan,Shu Li,Yang Xu,Ting Li,An‐Hua Li,Xiao‐Qiang Qiu,Yue‐Li Nan,Xiao‐Yun Zeng

doi:10.1002/cam4.1067

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.

Highlights

Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed cancers and the leading causes of cancer death worldwide
The results demonstrated that Barcelona Clinic Liver Cancer (BCLC) staging, SMAD3 rs11556090, and RBL2 rs3929 were still significantly associated with disease-free survival (DFS) of HCC patients (Table 4)
Data of Asian population from the HapMap 3 Project showed no significant association for neither rs11556090 nor rs3929 with their corresponding gene expression levels (P = 0.486 and 0.686, respectively, Fig. 2E and F). In this hypothesis-driven study, we identified SMAD3 rs11556090 A>G and RBL2 rs3929 G>C in the cell cycle pathway may independently or jointly modulate DFS of HCC patients

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed cancers and the leading causes of cancer death worldwide. A series of studies reported that the HCC patients survival was associated with SNPs in genes functioning in pivotal biological pathways or processes, such as cytokine genes [12, 13], telomere maintenance genes [14], DNA repair genes [15], Wnt/β-catenin pathway genes [16] These pieces of evidence demonstrate that genetic variants act as indicators of different processes of HCC and may provide further information beyond current clinical staging and pathologic prognostic assessments. We hypothesized that genetic variants in cell cycle pathway genes are associated with survival of HCC patients To test this hypothesis, we evaluated the associations of potential functional SNPs in 16 main cell cycle pathway genes (CDC25C, CDC7, CDKN1A, CDKN2A, CHEK1, MCM4, MCM7, MYC, ORC6L, KAT2B, PLK1, RAD21, RBL2, SMAD3, TGFB3, and YWHAB) with clinical outcomes of 271 HCC cases who had undergone radical surgery resection

Materials and Methods

Statistical methods

Results

Discussion