Tang Hui, Qiao Caixia, Guo Zhenwei, Geng Ruixuan, Sun Zhao, Wang Yingyi, Bai Chunmei
Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Department of Medical Oncology, Liaocheng Third People's Hospital, Liaocheng, China.
Heliyon. 2023 Jul 11;9(7):e18136. doi: 10.1016/j.heliyon.2023.e18136. eCollection 2023 Jul.
Necroptosis is associated with oncogenesis, tumor immunity and progression. This research aims to investigate the association of necroptosis-related genes with drug sensitivity and prognosis in hepatocellular carcinoma (HCC).
Based on necroptosis-related signatures, HCC patients retrieved from the TCGA database were categorized. Survival outcomes, mutation profile, immune microenvironment, and drug sensitivity between HCC subtypes were further compared. Then, LASSO analysis was performed to construct a necroptosis-related prognostic signature, which was further evaluated using another independent cohort.
A total of 371 patients with HCC could be categorized into two necroptosis-related subtypes. About 36% of patients were allocated to subtype A, with worse survival, more mutant TP53, and a lower likelihood of immunotherapy response. In contrast, patients in subtype B had a favorable prognosis, with lower expression of immunosuppressive signatures but a lower abundance of B and CD8 T-cell infiltration. The prognostic risk score calculated using the expression levels of nine genes involved in the necroptosis pathway (MLKL, FADD, XIAP, USP22, UHRF1, CASP8, RIPK3, ZBP1, and FAS) showed a significant association with tumor stage, histologic grade, and Child‒Pugh score. Additionally, the risk score model was proven to be accurate in both the training and independent external validation cohorts and performed better than the TNM staging system and three well-recognized risk score models.
Based on necroptosis-related signatures, we identified two HCC subtypes with distinctive immune microenvironments, mutation profiles, drug sensitivities, and survival outcomes. A novel well-performing prognostic model was further constructed.
坏死性凋亡与肿瘤发生、肿瘤免疫及进展相关。本研究旨在探讨坏死性凋亡相关基因与肝细胞癌（HCC）药物敏感性及预后的关系。
基于坏死性凋亡相关特征，对从TCGA数据库检索出的HCC患者进行分类。进一步比较HCC亚型之间的生存结局、突变谱、免疫微环境及药物敏感性。然后进行LASSO分析以构建坏死性凋亡相关预后特征，并使用另一个独立队列进行进一步评估。
总共371例HCC患者可分为两种坏死性凋亡相关亚型。约36%的患者被分配到A亚型，其生存较差，TP53突变更多，免疫治疗反应的可能性较低。相比之下，B亚型患者预后良好，免疫抑制特征表达较低，但B细胞和CD8 T细胞浸润丰度较低。使用坏死性凋亡途径中涉及的9个基因（MLKL、FADD、XIAP、USP22、UHRF1、CASP8、RIPK3、ZBP1和FAS）的表达水平计算的预后风险评分与肿瘤分期、组织学分级和Child-Pugh评分显著相关。此外，风险评分模型在训练队列和独立外部验证队列中均被证明是准确的，并且比TNM分期系统和三个公认的风险评分模型表现更好。
基于坏死性凋亡相关特征，我们鉴定出两种具有独特免疫微环境、突变谱、药物敏感性和生存结局的HCC亚型。进一步构建了一个性能良好的新型预后模型。
