染色体杂合性缺失在TNMI期肝细胞癌分子分期预后评估中的价值

The prognostic value of chromosomal loss of heterozygosity in molecular staging for TNM stage I of hepatocellular carcinoma

目的探讨染色体杂合性缺失（LOH）在TNMI期肝细胞癌（HCC）分子分期预后评估中的价值。方法对1999年1月至2000年3月131例行根治术的TNMI期HCC石蜡标本应用微切割技术，获取纯净肿瘤DNA进行LOH检测。选取1P、8p、17p、4q、13q及16q6条染色体上24个具有高度多态性的微卫星标记。分析LOH与TNMI期HCC患者根治术后5年总体生存（OS）、无瘤生存（DFS）的关系。结果LOH在检测的染色体位点上发生明显，D8S298位点、D1S199位点LOH频率分别为31．5％、33．7％。在单因素分析中，D8S298位点LOH的患者根治术后5年OS、DFS率皆明显低于无LOH的患者（46±5比62±2，P〈0．05；44±5比57±3，P〈0．05）。同样，在D1S199基因位点，LOH患者术后5年OS、DFS率亦显著低于无LOH者（42±4比61±2，P〈0．05；41±5比57±3，P〈0．05）。在多因素分析中，Cox比例风险模型显示D8S298位点LOH是TNMI期HCC患者根治术后DFS较差的独立因素（HR=0．372；95％CI=0．146—0．948；P〈0．05），而D1S199位点LOH是TNMI期HCC患者根治术后OS较差的独立因素（HR=0．281；95％CI=0．123～0．643；P〈0．05）。结论D8S298、D1S199位点LOH可以作为TNMI期HCC根治术后新型的预后预测分子标记，对TNMI期HCC的分子分期具有重要价值。

Objective To explore the prognostic value of chromosomal loss of heterozygosity （LOH） in molecular staging for tumor-node-metastasis （TNM） stage I of hepatocellular carcinoma （HCC） using survival analysis. Methods 131 patients with TNM stage I of FICC who underwent curative liver re- section from January 1999 to March 2000 were enrolled. Genomic DNA was extracted from the microdissec- ted HCC paraffin-embedded tissue samples for LOH detection using 24 high-pdymorphic microsatellite mar- kers located at chromosomes lp, 8p, 17p, 4q, 13q, and 16q, and its associations with the 5-year overall survival （OS） and the disease-free survival （DFS） of these patients were analyzed. Results LOH was fre- quent at the chromosomal loci analyzed. The LOH frequencies at D85298 and D1S199 were 31.5% and 33.7% , respectively. On univariate analysis, D8S298 LOH in the entire cohort was associated with a signi- ficantly worse 5-year OS （46 ± 5 vs. 62 ± 2, P 〈 0. 05） and DFS （44 ± 5 vs. 57 ± 3, P 〈 0. 05）. Likewise, patients with D1 S199 LOH had significantly worse 5-year OS （42 ± 4 vs. 61 ± 2, P 〈 0.05 ） and DFS （41 ± 5 vs. 57 ± 3, P 〈 0.05） than those without. On multivariate analyses, LOH at D8S298 was an independent predictor of decreased DFS （ HR = 0. 372 ; 95 % C1 = 0. 146 ± 0. 948 ; P 〈 0.05 ） , whereas LOH at D1 S199 was an independent predictor of decreased OS （ HR = 0. 281 ; 95% CI = 0. 123 - 0. 643 ; P 〈 0. 05 ）. Conclusion LOH at D8S298 and D1S199 could serve as novel biomarkers of prognostic prediction for pa- tients with TNM stage I of YtCC after curative liver resection, and it would be of great value in molecular staging for TNM stage I of HCC.