肝癌术后无转移生存相关的基因拷贝数变异分析  

Copy number aberrations of genes related to extrohepatic metastasis-free survival after operation for hepatocellular carcinoma

作　　者：鲍玲玲[1] 朱忠政[1] 闻炳基[1] 万小希 叶映泉 陈律[2] 贺松琴[1] 丛文铭[3] 

机构地区：[1]安徽医科大学宁波临床学院解放军第一一三医院肿瘤科,宁波315040 [2]宁波大学医学院,315211 [3]第二军医大学东方肝胆外科医院病理科,上海200438

出　　处：《中华肝脏病杂志》2017年第5期349-353,共5页Chinese Journal of Hepatology

基　　金：南京军区医学科技创新基金（14ZD07、08MA023）;宁波自然科学基金（2009A610126）

摘　　要：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％口为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。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 （/-~ = 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.

关 键 词：癌 肝细胞 肿瘤转移 基因 拷贝数变异 

分 类 号：R735.7[医药卫生—肿瘤]