肝细胞癌远处转移相关DNA拷贝数变异的全基因组分析

Genome-wide association analysis of DNA copy number alteration with distant metastasis in hepatocellular carcinoma

目的探讨与肝细胞癌(HCC)远处转移相关的DNA拷贝数变异(copy number alteration,CNA)分子标志。方法采用高分辨率Agilent 244K微阵列比较基因组杂交(aCGH)方法检测63例HCC样本基因组DNA的CNA特征。以Log-rank检验、Kaplan-Meier生存分析以及Cox风险比例模型,分析各DNA片段CNA与HCC远处转移的相关性。结果染色体片段12p12.2-13.31丢失是HCC患者远处转移的显著危险因素(P<0.01,Log-rank检验)。与非丢失者相比,12p12.2-13.31丢失HCC患者的远处转移风险比(hazard ratio,HR)为22.98(95%CI=4.29～123.22,P<0.01)。多变量Cox回归分析显示,12p12.2-13.31丢失是HCC远处转移的独立预测因素(HR=7.94,95%CI=1.14～55.61,P<0.05)。结论染色体片段12p12.2-13.31丢失增加HCC远处转移风险,可作为预测HCC远处转移的一个分子标志。

Objective To screen for DNA copy number alterations （CNAs） with potential value in predicting distant metastasis in hepatocellular carcinoma. Methods The genomic CNA status in 63 HCC samples was detected by high-resolution Agilent 244K comparative genomic hybridization oligoarrays. The hybridization data were analyzed using Agilent G2565BA and Feature Extraction 9. 5 software. The associations between CNAs and distant metastasis were analyzed using Log-rank test, Kaplan-Meier survival analysis and Cox proportional hazards models. Results Univariate association analyses revealed that the loss on 12p12.2-13.31 was significantly associated with distant metastasis in HCCs （P〈0.01, Log-rank test）. HCC cases with 12p12.2-13.31 loss had a 22.98-fold （95%CI = 4.29-123.22, P〈0.01） increased hazard ratio （HR） for distant metastasis, as compared to those without the loss. A Cox proportional hazards regression model including 12p12.2-13.31 loss, as well as clinicopathological variables such as age, gender. Edmondson- Steiner grade, complete envelope, cancer thrombi, and tumor stage identified 12p12.2-13.31 loss as an independent predictive marker for distant metastasis （HR = 7.94, 95%CI = 1.14-55.61, P〈0.05）. Conclusion Copy number loss of chromosome fragment 12p12.2-13.31 is associated with distant metastasis, implicating 12p12.2-13.31 loss as a valuable marker for the prediction of distant metastasis in HCC.