Construction and validation of prognostic risk model for patients with hepatocellular carcinoma based on bioinformatics analysis
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摘要:目的 利用公共数据库构建用于临床治疗肝细胞癌(HCC)的预后风险模型。方法 分别从癌症基因组图谱(TCGA)和国际癌症基因组联盟(ICGC)下载HCC以及癌旁正常组织的mRNA表达数据及临床信息。在TCGA队列中筛选与总生存期(OS)相关的差异表达基因(DEGs), 从中抽取2个或3个mRNAs构成一个组合, 对所有组合进行Cox风险比例回归模型构建。通过受试者工作特征(ROC)曲线的曲线下面积(AUC)确定最优基因组合，并进行基于ICGC队列的外部验证; 以TCGA队列的风险评分中位值将患者分为高风险组与低风险组，进行基因集富集分析(GSEA), 并通过pRRophetic R软件包预测HCC患者使用索拉非尼、丝裂霉素、依托泊苷、阿霉素、紫杉醇和顺铂的相对半抑制浓度(IC50)。结果 该预后风险模型预测TCGA队列的1、3、5年OS的ROC的AUC分别是0.786、0.713、0.699, 预测ICGC队列的1、3、4年OS的ROC的AUC分别为0.719、0.709、0.766。GSEA表明高风险组患者细胞周期相关通路被激活，胆汁酸代谢被抑制。索拉非尼在低风险组的IC50低于高风险组，而细胞周期相关化疗药物在低风险组的IC50高于高风险组，差异均有统计学意义(P < 0.05)。结论 本研究建立并验证了HCC预后风险模型，为HCC患者个体化诊疗方案的制订提供参考依据。Abstract:Objective To construct a prognostic risk model for clinical treatment of hepatocellular carcinoma (HCC) based on public databases.Methods The mRNA expression data and clinical information of HCC and adjacent normal tissues were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). Differentially expressed genes (DEGs) related to overall survival (OS) were screened in the TCGA cohort, 2 or 3 mRNAs were selected to form a combination, and Cox risk proportional regression model was constructed for all combinations. The optimal gene combination was determined by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve, and external validation based on ICGC cohort was carried out. The patients were divided into high-risk group and low-risk group according to the median risk score of TCGA cohort, gene set enrichment analysis (GSEA) was performed, and the relative half-inhibitory concentrations (IC50) of sorafenib, mitomycin, etoposide, adriamycin, paclitaxel and cisplatin in HCC patients were predicted by pRRophetic R software package.Results For this prognostic risk model, the AUC of the ROC curve for predicting 1-, 3- and 5-year OS in the TCGA cohort were 0.786, 0.713 and 0.699, respectively, and the AUC of the ROC curve for predicting 1-, 3- and 4-year OS in the ICGC cohort were 0.719, 0.709 and 0.766, respectively. GSEA revealed that cell cycle related pathways were activated and bile acid metabolism was inhibited in the high-risk group. The IC50 of sorafenib in the low-risk group was significantly lower than that in the high-risk group, while the IC50 of cell cycle related chemotherapy drugs in the low-risk group was significantly higher than that in the high-risk group (P < 0.05).Conclusion This study establishes and verifies the prognostic risk model for HCC, and provides a reference for the formulation of individualized diagnosis and treatment plan for HCC patients.
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图 1 最优基因组合分析
A: 与OS相关的差异基因的维恩图; B: BRSK1、KPNA2、HOXD9均在HCC组织中高表达;
C: BRSK1、KPNA2、HOXD9与TCGA队列患者OS的单因素Cox分析。![]()
图 2 模型预测HCC患者生存情况图
A: TCGA队列中风险评分的分布及其中位值; B: TCGA队列中生存状态、生存时间和风险评分的分布; C: TCGA队列中高风险组患者与低风险组患者OS的比较; D: 时间依赖性ROC曲线的AUC评估风险评分预测TCGA队列患者OS的表现; E: ICGC队列中风险评分的分布及其中位值; F: ICGC队列中生存状态、生存时间和风险评分的分布; G: ICGC队列中高风险组患者与低风险组患者OS的比较; H: 时间依赖性ROC曲线的AUC评估风险评分预测ICGC队列患者OS的表现。
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图 3 风险评分、临床病理资料与OS的相关性分析图
A、B: 风险评分、临床病理资料与TCGA队列患者OS的单因素及多因素Cox分析; C、D: 风险评分、临床病理资料与ICGC队列患者OS的单因素及多因素Cox分析。
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图 4 基于TCGA队列构建的预测HCC患者OS的列线图
A: 预测TCGA队列患者OS的列线图; B: 列线图基于TCGA队列的内部验证; C: 列线图基于ICGC队列的外部验证。
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图 6 TCGA队列高、低风险组患者对化疗及靶向药物的敏感度
A: 2组索拉非尼的相对IC50; B: 2组丝裂霉素的相对IC50; C: 2组依托泊苷的相对IC50; D: 2组阿霉素的相对IC50; E: 2组紫杉醇的相对IC50; F: 2组顺铂的相对IC50。
表 1 HCC患者的临床病理资料[n(%)]
临床资料 TCGA队列
(n=365)ICGC队列
(n=231)年龄/岁 61(16, 90) 69(31, 89) 性别 女 119(32.6) 61(26.4) 男 246(67.4) 170(72.6) 肿瘤分级 Ⅰ级 55(15.1) — Ⅱ级 175(47.9) — Ⅲ级 118(32.3) — Ⅳ级 12(3.3) — 未知 5(1.4) — 肿瘤分期 Ⅰ期 170(46.6) 36(15.6) Ⅱ期 84(23.0) 105(45.5) Ⅲ期 83(22.7) 71(30.7) Ⅳ期 4(1.1) 19(8.2) 未知 24(6.6) 0 血管浸润 有 106(29.0) — 无 205(56.2) — 未知 54(14.8) — 甲胎蛋白 ≤200 ng/mL 201(55.1) — > 200 ng/mL 75(20.5) — 未知 89(24.4) — 年龄以中位数(最小值，最大值)表示。 
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表 2 风险评分与HCC患者临床病理资料的相关性
临床资料 TCGA队列 ICGC队列 高风险组 低风险组 P 高风险组 低风险组 P 性别 0.80 1.00 女性 58 61 22 39 男性 125 121 62 108 年龄 0.80 0.42 < 60岁 81 84 29 60 ≥60岁 102 98 55 87 肿瘤分级 < 0.05 - 1、2级 134 96 - - 3、4级 47 83 - - 肿瘤分期 < 0.05 < 0.05 Ⅰ、Ⅱ期 141 113 63 78 Ⅲ、Ⅳ期 30 57 21 69 血管浸润 < 0.05 - 无 124 81 - - 有 44 62 - - 甲胎蛋白 < 0.05 - ≤200 ng/mL 122 79 - - >200 ng/mL 27 48 - -
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