染色体17q区拷贝数变异与肝细胞癌总生存的相关性及靶基因的筛选

Association of chromosome 17q copy number variation with overall survival of patients with hepatocellular carcinoma and screening of potential target genes

目的探讨染色体17q拷贝数变异（copynumbervariation，CNV）与肝细胞癌（hepatocellularcarcinoma，HCC）术后总生存（overallsurvival，OS）的相关性以及预后相关CNV内的潜在靶基因。方法纳入HCC手术患者174例，其中66例有完整术后OS随访资料。应用AgilentHu-244A微阵列比较基因组杂交和AffymetrixU133Plus2．0表达芯片分别检测染色体17qCNV和基因表达。结果17q25．1—25．3增益与0S显著相关（P一0．00002）。多因素Cox回归分析显示，17q25．1-25．3增益是0S的独立不良预后因素（HR：3．17，95％CI：1.39～7。26，P=0。006）。基因CNV与mRNA表达的联合分析显示，SLC9A3R1、GRB2、TK1等18个基因mRNA表达水平在基因增益HCC中显著高于基因无增益HCC（FDR-q〈0．05，P〈0．01）及癌旁肝组织（P〈0．01）。结论17q25．1.25．3增益与HCC不良预后有关，可作为HCC的一个预后预测因子。SLC9A3R1、GRB2、TK1基因可能是17q25．1-25．3增益的潜在靶基因。

Objective To assess the association of copy number variations （CNVs） in chromosome 17q with the overall survival（OS） of patients with hepatocellular carcinoma（HCC）, and to screen for target genes contained in the OS-related CNVs. Methods A total of 174 HCC cases were enrolled. For 66 patients, the follow-up data was available. High-resolution Agilent Hu-244A array comparative genomic hybridization （aCGH） and Affymetrix U133 Plus 2.0 expression arrays were used to detect CNVs and gene expression of genes from the 17q region, respectively. The association of CNVs and OS was assessed with Log-rank test, Kaplan-Meier survival analysis, and Cox proportional hazards models. The gene expression in HCCs with 17q gain, HCCs without, and non-tumor liver tissues were compared with a Mann-Whitney U test. Results Llnivariate association analysis showed that copy number gain in 17q25. 1-25. 3 was significantly associated with reduced OS （Log-rank test, P=0. 000 02）, and HCC cases with 17q25.1-25.3 gain had a 4.76-fold （95%Ch 2.31-9.81） increased hazard ratio （HR） for death from HCC, as compared to those without the gain. Multivariate Cox proportional hazards regression model revealed 17q25.1-25.3 gain to be an independent prognostic marker for poor OS （HR=3.17, 95%CI： 1.39-7.26, P=0. 006）. The expression levels of 18 genes in 17q25. 1-25. 3 including SLC9A3R1, GRB2, and TK1 were significantly increased in HCCs with gain than in those without （all P〈0.01） and non-tumor liver tissues （all P〈0.01）. Conclusion The association of 17q25. 1-25. 3 gain with reduced OS has indicated that it is a prognostic marker for poor patient survival in HCC, for which SLC9A3R1, GRB2, and TK1 are candidate genes.