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摘要：
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摘要：目的 分析肝癌患者NOP2基因状态对免疫治疗疗效及预后的影响。方法 以2017年
6月至2020年6月于河北省定州市人民医院住院治疗的157例肝癌患者为研究对象，根
据NOP2基因状态分为NOP2突变组（56例）和NOP2野生组（101例）。比较两组患者
的临床资料 [包括性别、年龄、体重指数（body mass index，BMI）、中国肝癌分期
（China clinic liver cancer staging，CNLC staging）、肝功能Child-Pugh分级、东部肿瘤
协作组（Eastern Cooperative Oncology Group，ECOG）评分等]、免疫治疗疗效 [客观
缓解率（objective response rate，ORR）、疾病控制率（disease control rate，DCR）] 及
预后情况。对患者随访3年，记录患者的总生存期（overall survival，OS）和无进展生
存期（progress free survival，PFS）。通过Kaplan-Meier法绘制生存曲线分析不同NOP2
基因状态肝癌患者的PFS和OS。通过单因素及多因素Cox回归分析影响患者PFS和OS的
因素。建立患者PFS和OS的列线图预测模型，采用受试者工作特征（receiver operating
characteristics，ROC）曲线、校准曲线和临床决策曲线对模型进行评价。结果 NOP2突
变组与NOP2野生组患者的Child-Pugh分级、CNLC分期、肿瘤直径、肿瘤数目和门静脉
侵犯的差异有统计学意义（P ＜ 0.05）。免疫治疗后NOP2突变组患者的ORR [60.71%
（34/56）比31.68%（32/101）] 和DCR [96.43%（54/56）比82.18%（83/101）] 均显
著高于NOP2野生组（P均＜ 0.05）。NOP2突变组患者的PFS及OS均显著高于NOP2
野生组（Log-Rank χ2 = 3.822，P = 0.033；Log-Rank χ2 = 4.741，P = 0.025）。多因素
Cox回归分析表明，Child-Pugh B级（HR = 2.120，95%CI：1.121～4.009，P = 0.021；
HR = 2.411，95%CI：1.203～4.833，P = 0.013）、CNLC Ⅳ期（HR = 4.904，95%CI：
2.070～11.617，P ＜ 0.001；HR = 3.167，95%CI：1.472～6.810，P = 0.003）、肿瘤直
径≥ 61.72 mm（HR = 3.065，95%CI：1.471～6.082，P ＜ 0.001；HR = 2.967，95%CI：
1.314～6.259，P ＜ 0.001）、肿瘤数目＞ 3个（HR = 3.374，95%CI：1.711～6.653，
P ＜ 0.001；HR = 2.358，95%CI：1.182～4.704，P = 0.015）、门静脉侵犯（HR =
3.176，95%CI：1.643～6.141，P = 0.001；HR = 3.173，95%CI：1.572～6.404，P ＜
0.001）是肝癌患者PFS和OS的独立危险因素，NOP2基因突变是保护因素（HR = 0.380，
95%CI：0.193～0.764，P = 0.005；HR = 0.346，95%CI：0.156～0.763，P = 0.009）。
PFS和OS预测模型的ROC曲线下面积分别为0.836（95%CI：0.769～0.887，P ＜
0.001）和0.794（95%CI：0.728～0.855，P ＜ 0.001），C-index分别为0.811（95%CI：
0.782～0.843）和0.786（95%CI：0.754～0.820），校准曲线拟合度均良好，临床决策曲
线阈值概率为0.1～0.9，净获益率均较高。结论 NOP2基因状态与肝癌患者的免疫治疗疗
效及预后有关，采用免疫治疗联合化学治疗可改善伴NOP2基因突变患者的预后。
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Abstract: Objective To investigate the effects of NOP2 gene status on immunotherapy
efficacy and prognosis of patients with liver cancer. Methods Total of 157 patients with
liver cancer hospitalized in People’s Hospital of Dingzhou from June 2017 to June 2020
were selected as the study subjects. According to the status of NOP2 gene, the patients
were divided into NOP2 mutation group (56 cases) and NOP2 wild group (101 cases).
The clinical data [including gender, age, body mass index (BMI), China clinic liver cancer
staging (CNLC staging), Child-Pugh score, Eastern Cooperative Oncology Group (ECOG),
etc.], immunotherapy efficacy [objective response rate (ORR), disease control rate (DCR)]
and prognosis of patients in two groups were compared. The patients were followed for
3 years, and their overall survival (OS) and progression-free survival (PFS) were recorded.
Kaplan-Meier method was used to plot survival curves and analyze PFS and OS of liver
cancer patients with different NOP2 gene states. Univariate and multivariate Cox regression
analysis were used to analyze the influence factors affecting PFS and OS in patients with
liver cancer. A monograms prediction model for PFS and OS was established, and receiver
operating characteristics (ROC) curve, calibration curve, and clinical decision curve were
used to evaluate the model. Results There were statistically significant differences between
patients in NOP2 mutant group and NOP2 wild group in terms of Child-Pugh grading,
CNLC staging, tumor diameter, number of tumors and portal vein invasion (all P ＜ 0.05).
After immunotherapy, the ORR [60.71% (34/56) vs. 31.68% (32/101)] and DCR [96.43%
(54/56) vs. 82.18% (83/101)] of patients in NOP2 mutant group were significantly higher
than those of NOP2 wild group (all P ＜ 0.05). PFS and OS of patients in NOP2 mutation
group were significantly higher than those of NOP2 wild group (Log-Rank χ2 = 3.822, P =
0.033; Log-Rank χ2 = 4.741, P = 0.025). Multivariate Cox regression analysis showed that
Child-Pugh grade B (HR = 2.120, 95%CI: 1.121～4.009, P = 0.021; HR = 2.411, 95%CI:
1.203～4.833, P = 0.013), CNLC staging Ⅳ (HR = 4.904, 95%CI: 2.070～11.617, P ＜ 0.001;
HR = 3.167, 95%CI: 1.472～6.810, P = 0.003), tumor diameter ≥ 61.72 mm (HR =3.065,
95%CI: 1.471～6.082, P ＜ 0.001; HR = 2.967, 95%CI: 1.314～6.259, P ＜ 0.001),
number of tumors ≥ 3 (HR = 3.374, 95%CI: 1.711～6.653, P ＜ 0.001; HR = 2.358, 95%CI:
1.182～4.704, P = 0.015), portal vein invasion (HR = 3.176, 95%CI: 1.643～6.141, P = 0.001;
HR = 3.173, 95%CI: 1.572～6.404, P ＜ 0.001) were influence factors affecting PFS and OS
in patients with liver cancer, and NOP2 gene mutation was a protective factor (HR = 0.380,
95%CI: 0.193～0.764, P = 0.005; HR = 0.346, 95%CI: 0.156～0.763, P = 0.009). The areas
under the ROC curves of the PFS and OS prediction models were 0.836 (95%CI: 0.769～0.887,
P ＜ 0.001) and 0.794 (95%CI: 0.728～0.855, P ＜ 0.001), respectively. The C-index were
0.811 (95%CI: 0.782～0.843) and 0.786 (95%CI: 0.754～0.820), respectively, the calibration
curve fits well, the net benefit rates was high when the threshold probability of the clinical
decision curve was within the range of 0.1～0.9. Conclusions The status of NOP2 gene was
related to the efficacy and prognosis of immunotherapy in patients with liver cancer. The
combination of immunotherapy and chemotherapy could improve the prognosis of patients
with NOP2 gene mutations.
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