Objective: To investigate the molecular markers of copy number aberrations (CNAs) of genes related to extrohepatic metastasis-free survival after the operation for hepatocellular carcinoma (HCC). Methods: The CNA status of 20 candidate genes in 66 HCC samples was detected by microarray comparative genomic hybridization. The associations between gene CNAs and extrohepatic metastasis-free survival were evaluated using the Cox regression model, Log-rank test, and Kaplan-Meier survival analysis. Results: Multivariate Cox analysis revealed that the independent risk factors for metastasis-free survival were MDM4 gain (hazard ratio [HR] = 2.74, 95% confidence interval [CI] = 1.18-6.37, P < 0.05), APC loss (HR = 8.43, 95% CI = 2.48-28.66, P < 0.01), and BCL2L1 gain (HR = 3.45, 95% CI = 1.13-10.52, P < 0.05) and the independent protective factor was FBXW7 loss (HR = 0.32, 95% CI = 0.12-0.89, P < 0.05). By stepwise Cox regression analysis, three CNAs related to metastasis-free survival were screened out: MDM4 gain (HR = 2.71, 95% CI = 1.11-6.64, P < 0.05), APC loss (HR = 7.19, 95% CI = 1.88-27.60, P < 0.005), and FBXW7 loss (HR = 0.16, 95% CI = 0.05-0.46, P < 0.01). There were significant differences in metastasis-free survival rate between the HCC patients with FBXW7 loss and without MDM4 gain or APC loss, those with MDM4 gain and/or APC loss and without FBXW7 loss, and those with other CNA combinations (log-rank test, P < 0.01). Conclusion: MDM4 gain, APC loss, and FBXW7 loss are the independent prognostic factors for extrohepatic metastasis-free survival after the operation for HCC and can be used to predict the risk of extrohepatic metastasis after the operation for HCC.
目的: 探讨肝细胞癌(HCC)术后无肝外转移生存相关的基因拷贝数变异(CNA)分子标志物。 方法: 采用微阵列比较基因组杂交技术检测66例HCC基因组DNA中的20个候选基因CNA,并与无肝外转移生存进行相关性分析。对数据采用Cox模型进行单因素、多因素及多元逐步回归生存分析。 结果: 多因素Cox分析显示,MDM4增益[风险比(HR)= 2.74, 95%可信区间(CI)为1.18~6.37 (P < 0.05)]、APC丢失(HR = 8.43, 95% CI为2.48~28.66, P < 0.01)和BCL2L1增益(HR = 3.45, 95% CI为1.13~10.52, P < 0.05)是无转移生存的独立危险因素,而FBXW7丢失(HR = 0.32, 95% CI为0.12~0.89, P < 0.05)是独立保护因素。多元逐步Cox回归分析筛出MDM4增益(HR = 2.71, 95% CI为1.11~6.64, P < 0.05)、APC丢失(HR = 7.19, 95% CI为1.88~27.60, P < 0.005)和FBXW7丢失(HR = 0.16, 95% CI为0.05~0.46, P < 0.01)等3个无转移生存相关CNAs。MDM4增益(-)/APC丢失(-)/FBXW7丢失(+)、MDM4增益(+)和(或)APC丢失(+)/FBXW7丢失(-)、其他组合等3组HCC患者术后无转移生存率差异有统计学意义(P < 0.01)。 结论: MDM4增益、APC丢失和FBXW7丢失是HCC术后无转移生存的独立预后因素,可用于HCC术后肝外转移的风险预判。.