Table3_A necroptosis -related signature for predicting prognosis and immunotherapy in hepatocellular carcinoma.XLS

Background: Hepatocellular Carcinoma (HCC) is an aggressive tumor with an inferior prognosis. Necroptosis is a new form of programmed death that plays a dual effect on the tumor. However, the role of necroptosis-related genes(NRGs) in HCC remains unknown.
Methods: All datasets were downloaded from publicly available databases. The consensus clustering analysis was used to classify patients into different subtypes based on NRGs. The Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression were used to develop a prognostic signature. Tumor Immune Dysfunction and Exclusion (TIDE) was used to predict immunotherapy response.
Results: The genetic and transcriptional changes of NRGs were observed in HCC. Patients were classified into three clusters based on differentially expressed NRGs, of which Cluster-3 had the worst prognosis and the highest immune infiltration. The prognostic signature was developed based on 8-NRGs, which have shown excellent prognostic performance. The high-risk group in the signature presented significantly higher immune infiltration, such as aDCs, iDCs, macrophages, and Treg, compared to the low-risk group. TMB and immune checkpoints were also higher in the high-risk group. Moreover, a lower TIDE score was observed in the high-risk group, indicating the patients with high risk-score may be suitable for immunotherapy. Via the dataset of IMvigor210, we found a higher risk score in the immunotherapy response group.
Conclusion: We developed a new necroptosis-related signature for predicting prognosis with the potential to predict immunotherapy for HCC patients.

背景：肝细胞癌（Hepatocellular Carcinoma, HCC）是一类侵袭性极强的肿瘤，患者预后欠佳。细胞坏死性凋亡（necroptosis）是一种新型程序性死亡方式，在肿瘤发生发展中发挥双重调控作用。然而，坏死性凋亡相关基因（necroptosis-related genes, NRGs）在肝细胞癌中的作用仍未明确。
方法：所有数据集均下载自公开可用数据库。本研究基于坏死性凋亡相关基因，通过共识聚类分析将患者划分为不同亚型；采用最小绝对收缩和选择算子（Least Absolute Shrinkage and Selection Operator, LASSO）Cox回归模型构建预后特征；使用肿瘤免疫功能异常与排斥（Tumor Immune Dysfunction and Exclusion, TIDE）工具预测患者的免疫治疗应答情况。
结果：研究观察到肝细胞癌组织中坏死性凋亡相关基因存在遗传与转录水平的异常改变。基于差异表达的坏死性凋亡相关基因，患者可被分为3个聚类亚型，其中聚类3的预后最差且免疫浸润水平最高。本研究基于8个坏死性凋亡相关基因构建了预后特征，该特征展现出优异的预后预测效能。相较于低风险组，特征评分高的患者组免疫浸润水平显著更高，包括活化树突状细胞（aDCs）、未成熟树突状细胞（iDCs）、巨噬细胞及调节性T细胞（Treg）等；同时高风险组的肿瘤突变负荷（Tumor Mutational Burden, TMB）与免疫检查点表达水平也更高。此外，高风险组的TIDE评分更低，提示高风险评分患者可能更适合接受免疫治疗。通过IMvigor210数据集分析发现，免疫治疗应答组的风险评分更高。
结论：本研究构建了一种新型坏死性凋亡相关预后特征，该特征可有效预测肝细胞癌患者的预后，同时具备预测患者免疫治疗获益的潜在价值。