Gene Copy Number Aberrations Related To Extrahepatic Metastasis-free Survival Of Postoperative Hepatocellular Carcinoma

ObjectiveHepatocellular carcinoma(HCC)is of low early diagnosis,poor prognosis and high mortality with about 700,000 people dying every year in the world.Postoperative HCC is extremely prone to intrahepatic recurrence and extrahepatic metastasis,leading to poor prognosis of the most important reasons.Compared with intrahepatic recurrence,we know little about molecular markers of extrahepatic metastasis.And it is difficult to judge the risk of postoperative metastasis in early stage of HCC,which has become one of the bottlenecks of clinical treatment decision.Copy number aberration(CNA)refers to sections of the genome gain or loss at the DNA level,and some crucial chromosome fragments CNAs are already known to be closely related to the prognosis of HCC.In the present study,we adopt candidate gene methods to explore the molecular markers of CNA related to extrahepatic metastasis-free survival.MethodsThe CNA status of 20 candidate genes in 66 HCC samples were detected by array comparative genomic hybridization.The follow-up data of all 66 HCC patients was 1.6-90.5 months.Extrahepatic metastasis-free survival was defined as the interval from surgery to extrahepatic metastasis or last follow-up time.The associations between gene CNAs and extrahepatic metastasis-free survival were tested using Cox regression model,Log-rank test and Kaplan-Meier survival analysis.Log-rank test was used to analyze the difference between survival curves.The associations between gene CNAs and clinicopathological variables were analyzed by Exact ?2 test.Two-side P < 0.05 were defined as statistically significant.All statistical analyses were performed with Stata 13.0.Results1.Univariate Cox analysis showed that MDM4 gain,APC loss,BCL2L1 gain,FBXW7 loss and ANXA10 loss were significantly associtated with metastasis-free survival of postoperative HCC(all P < 0.05);History of hypertension,platelet counts,prothrombin time,complete tumor capsule and TNM stage were also significantly associtated with metastasis-free survival of postoperative HCC(all P < 0.05).2.Multivariate Cox analysis revealed that MDM4 gain,APC loss and BCL2L1 gain were independent risk prognostic markers for metastasis-free survival,while FBXW7 loss was an independent protective marker.3.The associations between gene CNAs and clinicopathological variables showed that MDM4 gain was related to sex,FBXW7 loss was related to prolonged prothrombin time.The relationships between APC loss,BCL2L1 gain and clinicopathological variables loss statistical significance.4.The multiple stepwise Cox regression revealed that MDM4 gain,APC loss,FBXW7 loss,the history of hypertension and high TNM stage were independent prognostic factors.MDM4 gain,APC loss,the history of hypertension and high TNM stage were risk factors,while FBXW7 loss was the protective factor.5.CNA combinations correlated with extrahepatic metastasis-free survival: The non-metastatic survival was significantly different between patients with FBXW7 loss together without MDM4 gain or APC loss,cases with MDM4 gain and/or APC loss together without FBXW7 loss,and those with other CNA combinations(Log-rank test,P = 0.0001).Conclusions1.MDM4 gain,APC loss and BCL2L1 gain were independent risk prognostic markers for metastasis-free survival,while FBXW7 loss was an independent protective marker.2.CNA combinations based on MDM4 gain,APC loss and FBXW7 loss could help to identify patients at higher risk for extrahepatic metastasis at the time of initial diagnosis of HCC,which provide a basis for clinical treatment decision-making and thus improve the prognosis of patients.