Lai Jinzhi, Yang Hainan, Xu Tianwen
Department of Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian, China.
Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
BMC Cancer. 2021 Jul 22;21(1):848. doi: 10.1186/s12885-021-08548-3.
Malignant mesothelioma (MM) is a relatively rare and highly lethal tumor with few treatment options. Thus, it is important to identify prognostic markers that can help clinicians diagnose mesothelioma earlier and assess disease activity more accurately. Alternative splicing (AS) events have been recognized as critical signatures for tumor diagnosis and treatment in multiple cancers, including MM.
We systematically examined the AS events and clinical information of 83 MM samples from TCGA database. Univariate Cox regression analysis was used to identify AS events associated with overall survival. LASSO analyses followed by multivariate Cox regression analyses were conducted to construct the prognostic signatures and assess the accuracy of these prognostic signatures by receiver operating characteristic (ROC) curve and Kaplan-Meier survival analyses. The ImmuCellAI and ssGSEA algorithms were used to assess the degrees of immune cell infiltration in MM samples. The survival-related splicing regulatory network was established based on the correlation between survival-related AS events and splicing factors (SFs).
A total of 3976 AS events associated with overall survival were identified by univariate Cox regression analysis, and ES events accounted for the greatest proportion. We constructed prognostic signatures based on survival-related AS events. The prognostic signatures proved to be an efficient predictor with an area under the curve (AUC) greater than 0.9. Additionally, the risk score based on 6 key AS events proved to be an independent prognostic factor, and a nomogram composed of 6 key AS events was established. We found that the risk score was significantly decreased in patients with the epithelioid subtype. In addition, unsupervised clustering clearly showed that the risk score was associated with immune cell infiltration. The abundances of cytotoxic T (Tc) cells, natural killer (NK) cells and T-helper 17 (Th17) cells were higher in the high-risk group, whereas the abundances of induced regulatory T (iTreg) cells were lower in the high-risk group. Finally, we identified 3 SFs (HSPB1, INTS1 and LUC7L2) that were significantly associated with MM patient survival and then constructed a regulatory network between the 3 SFs and survival-related AS to reveal potential regulatory mechanisms in MM.
Our study provided a prognostic signature based on 6 key events, representing a better effective tumor-specific diagnostic and prognostic marker than the TNM staging system. AS events that are correlated with the immune system may be potential therapeutic targets for MM.
恶性间皮瘤（MM）是一种相对罕见且致死率高的肿瘤，治疗选择有限。因此，识别能够帮助临床医生更早诊断间皮瘤并更准确评估疾病活动的预后标志物非常重要。可变剪接（AS）事件已被认为是包括MM在内的多种癌症中肿瘤诊断和治疗的关键特征。
我们系统地研究了来自TCGA数据库的83个MM样本的AS事件和临床信息。采用单变量Cox回归分析来识别与总生存期相关的AS事件。进行LASSO分析，随后进行多变量Cox回归分析以构建预后特征，并通过受试者工作特征（ROC）曲线和Kaplan-Meier生存分析评估这些预后特征的准确性。使用ImmuCellAI和ssGSEA算法评估MM样本中免疫细胞浸润程度。基于生存相关的AS事件与剪接因子（SFs）之间的相关性建立生存相关剪接调控网络。
通过单变量Cox回归分析共鉴定出3976个与总生存期相关的AS事件，其中外显子跳跃（ES）事件占比最大。我们基于生存相关的AS事件构建了预后特征。该预后特征被证明是一种有效的预测指标，曲线下面积（AUC）大于0.9。此外，基于6个关键AS事件的风险评分被证明是一个独立的预后因素，并建立了由6个关键AS事件组成的列线图。我们发现上皮样亚型患者的风险评分显著降低。此外，无监督聚类清楚地表明风险评分与免疫细胞浸润有关。高风险组中细胞毒性T（Tc）细胞、自然杀伤（NK）细胞和辅助性T细胞17（Th17）细胞的丰度较高，而诱导调节性T（iTreg）细胞在高风险组中的丰度较低。最后，我们鉴定出3个与MM患者生存显著相关的SFs（HSPB1、INTS1和LUC7L2），然后构建了这3个SFs与生存相关AS之间的调控网络，以揭示MM中的潜在调控机制。
我们的研究提供了基于6个关键事件的预后特征，与TNM分期系统相比，它是一种更有效的肿瘤特异性诊断和预后标志物。与免疫系统相关的AS事件可能是MM的潜在治疗靶点。
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