肝细胞癌患者术后复发相关的6号染色体短臂拷贝数变异及靶基因

Copy number alterations and target genes in chromosome 6 short arm were related to postoperative recurrence of patients with hepatocellular carcinoma

目的探讨染色体6p拷贝数变异（CNA）与肝细胞癌（HCC）术后肝内复发的相关性，探讨相关靶基因。方法采用微阵列比较基因组杂交和表达芯片分别检测CNAs和基因表达。6p CNAs与66例HCC复发的相关性采用生存分析。117例HCC的差异表达基因分析采用Mann-Whitney U检验。结果在66例HCC中，46例（69．7％）呈现6p CNAs。在8个高频（发生率〉20％）CNAs中，6p21．1增益是复发（HR=2．3，95％CI=1．1～5．1，P〈0．05），特别是近期复发（≤1年；HR=3．5，95％CI=1．4～8．2，P〈0．05）的独立预后因素。片段内BYSL、RPL7L1等9个基因表达水平在6p21．1增益组高于无增益组（均P〈0．05）。BYSL高表达与肿瘤直径大于6cm、血管侵犯和高肿瘤分期有关（均P〈0．05）；RPL7L1高表达与血管侵犯和高肿瘤分期有关（均P〈0．05）。结论6p21．1增益是HCC术后肝内复发特别是近期复发的独立预后因素，BYSL和RPLTL1可能是靶基因。

Objective -To investigate the relationship-between chromosome 6p copy number altera-tions （CNAs） and postoperative intrahepatic recurrence of hepatocellular carcinoma （ HCC ） ; and to screen for the target genes in CNA（s）. Methods Array comparative genomic hybridization （CGH） and expression arrays were used to detect CNAs and differences in gene expression, respectively. The associations between CNAs in 6p and HCC recurrence were analyzed using the log-rank test, the Kaplan-Meier curves and the Cox proportional hazards models on 66 patients who had been follow-up for 2.6 - 73.3 months. The differentially expression of genes in the potentially recurrence-related CNAs were further evaluated by the Mann- Whitney U test on 117 HCCs, which included 109 cases with paired array CGH and expression data. Results 6p CNAs were detected in 46 （69, 7% ） of the 66 HCCs. Of the 8 CNAs with the most frequent recurrence of over 20% , a gain at 6p21. 1 was independently associated with a 2. 3-fold （95% CI = 1.1 - 5. 1, P 〈 0. 05 ） increased risk for intrahepatic recurrence and with a more pronounced 3.3-fold （ 95% CI = 1.4 - 8.2, P 〈0. 05） risk for early recurrence （≤ 1 year）. A panel of 9 genes, including BYSL and RPL7L1 within the documented 6p21.1, were observed to be upregulated in HCCs with 6p21.1 gain when compared with HCCs without （ all P 〈 0.05）. A high BYSL expression significantly correlated with a larger tumor size （ 〉 6 cm） , vascular invasion and advanced tumor stage （all P 〈 0. 05 ） , and high RPL7LI expression significantly correlated with vascular invasion and advanced tumor stage （ all P 〈 0. 05 ）. Conclusion A gain at 6p21.1 was an independently prognostic marker for intrahepatie recurrence of postoperative HCC, particular for early recurrence, and BYSL and RPL7L1 might be the target genes in the recurrence-related 6p21.1 gain.