基于铜死亡相关基因标签预测肝细胞癌的预后、药物敏感性及免疫治疗反应

A novel cuproptosis-related gene signature for prediction of prognosis,drug sensitivity and immunotherapy response in patients with hepatocellular carcinoma

目的构建铜死亡相关基因标签(CRGS),基于CRGS预测肝细胞癌(HCC)患者的预后、免疫治疗反应及药物敏感性。方法从国际癌症基因组联盟(ICGC)和癌症基因组图谱(TCGA)数据库下载HCC患者的RNA测序和相应的临床数据,从人类蛋白质图谱图像分类(HPA)数据库获得肝癌组织和正常肝脏组织的蛋白表达信息,并从Migort210数据库下载HCC患者的基因表达信息和免疫治疗反应情况。基于TCGA队列,应用最小绝对值收敛和选择算法(LASSO)构建CRGS,计算每个样本的风险分数,根据风险分数的中位数对HCC患者进行分组:TCGA队列分为高风险组_(TCGA)和低风险组_(TCGA),每组184例;ICGC队列分为高风险组_(ICGC)和低风险组_(ICGC),每组116例。在Migort210队列中根据免疫治疗应答反应分为应答组(n=68)和非应答组(n=230)。评估CRGS预判TCGA队列中HCC患者预后的价值。在ICGC数据集中验证CRGS是否可用于预测HCC患者的预后。基于TCGA队列的数据,探讨CRGS预测HCC患者免疫治疗反应、药物敏感性的作用,同时应用Migort210免疫治疗队列验证CRGS预测恶性肿瘤免疫治疗中的临床价值。结果CRGS由4个铜死亡相关基因构成:GLS、CDKN2A、LIPT1和DLAT。高风险组_(TCGA)患者的总生存期(OS)、疾病特异性生存期和无进展间期均低于低风险组_(TCGA)(均P<0.01)。高风险组_(ICGC)患者的OS低于低风险组_(ICGC)(P=0.022)。多因素Cox回归分析结果显示,CRGS是HCC患者不良预后的的独立危险因素(TCGA:HR=2.991,95%CI:1.781~5.049,P<0.001;ICGC:HR=4.621,95%CI:1.685~12.674,P=0.033)。风险分数与CTLA4、PDCD1、CD80和HLLA2的表达量呈正相关(均P<0.001)。高风险组_(TCGA)患者的肿瘤免疫功能障碍与排斥评分低于低风险组_(TCGA)[-0.04(-0.07,-0.02)分比-0.02(-0.04,0)分],差异具有统计学意义(P<0.001)。应答组患者的风险分数高于非应答组[1.70(1.56,1.90)比1.63(1.52,1.80)],差异具有统计学意义(P<0.05)。高风险组_(TCGA)患者对于舒尼替尼、雷帕霉素和乙胺嘧啶的半数抑制浓度(IC_(50))高于低风险组_(TCGA)患者,而对厄洛替尼的IC_(50)低于低风险组_(TCGA)患者,差异均具有统计学意义(均P<0.001)。结论CRGS可作为预测HCC患者预后、免疫治疗反应及药物敏感性的潜在生物标志物。

Objective To construct a novel cuproptosis-related gene signature(CRGS)for prediction of prognosis,immunotherapy response and drug sensitivity in patients with hepatocellular carcinoma(HCC).Methods Data materials for this study were obtained from the international cancer genome consortium(ICGC),the cancer genome atlas(TCGA)database and Migort210 database,and protein expression profiles were obtained from the human protein atlas image classification database.Based on the TCGA cohort,the least absolute shrinkage and selection operator algorithm was applied to construct the CRGS and calculate the risk score for each HCC patient.HCC patients were grouped according to the median risk score:HCC patients in the TCGA cohort were divided into a high-risk group_(TCGA) and a low-risk group_(TCGA) with 184 cases in each group;HCC patients in the ICGC cohort were divided into a high-risk group_(ICGC) and a low-risk group_(ICGC) with 116 cases in each group.Patients in the Migort210 cohort were divided into a responder group(n=68)and a non-responder group(n=230)based on their response to immunotherapy.We assessed the value of CRGS in predicting the prognosis of HCC patients in the TCGA cohort and validated whether CRGS could be used to predict the prognosis of HCC patients in the ICGC dataset.To explore the role of CRGS in predicting immunotherapy response and drug sensitivity in HCC patients based on data from the TCGA cohort,and to apply the Migort210 immunotherapy cohort to validate the clinical value of CRGS in predicting immunotherapy in malignant tumors.Results CRGS consists of four copper death-related genes:GLS,CDKN2A,LIPT1,and DLAT.Patients in the high-risk group_(TCGA) had lower overall survival(OS),disease-specifical survival,and progression-free interval than those in the low-risk group_(TCGA)(all P<0.01).OS of patients in the high-risk group_(ICGC) was lower than that in the low-risk group_(ICGC)(P=0.022).Multivariate Cox regression analysis showed that CRGS was an independent risk factor for poor prognosis in HCC patients(TCGA:HR=2.991,95%CI:1.781-5.049,P<0.001;ICGC:HR=4.621,95%CI:1.685-12.674,P=0.033).Risk scores were positively correlated with the expression levels of CTLA4,PDCD1,CD80 and HLLA2(all P<0.001).Patients in the high-risk group_(TCGA) had lower tumor immune dysfunction and rejection scores than those in the low-risk group_(TCGA)[-0.04(-0.07,-0.02)vs.-0.02(-0.04,0)points],and the difference was statistically significant(P<0.001).Patients in the responder group had a higher risk score than the non-responder group[1.70(1.56,1.90)vs.1.63(1.52,1.80)],with a statistically significant difference(P<0.05).The half-inhibitory concentrations(IC_(50))for sunitinib,rapamycin and etanercept were higher in the high-risk group_(TCGA) than that in the low-risk group_(TCGA),while the IC_(50) for erlotinib was lower than that in the low-risk group_(TCGA),and the differences were all statistically significant(all P<0.001).Conclusion The CRGS might be served as a potential biomarker to predict the prognoses,immunotherapy response,and drug sensitivity of patients with HCC.