Wang Zhihao, Embaye Kidane Siele, Yang Qing, Qin Lingzhi, Zhang Chao, Liu Liwei, Zhan Xiaoqian, Zhang Fengdi, Wang Xi, Qin Shenghui
Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Pharmacy, Hiser Medical Center of Qingdao, Qingdao, 266033, China.
Cancer Cell Int. 2021 Apr 15;21(1):219. doi: 10.1186/s12935-021-01915-x.
Given that dysregulated metabolism has been recently identified as a hallmark of cancer biology, this study aims to establish and validate a prognostic signature of lung adenocarcinoma (LUAD) based on metabolism-related genes (MRGs).
The gene sequencing data of LUAD samples with clinical information and the metabolism-related gene set were obtained from The Cancer Genome Atlas (TCGA) and Molecular Signatures Database (MSigDB), respectively. The differentially expressed MRGs were identified by Wilcoxon rank sum test. Then, univariate cox regression analysis was performed to identify MRGs that related to overall survival (OS). A prognostic signature was developed by multivariate Cox regression analysis. Furthermore, the signature was validated in the GSE31210 dataset. In addition, a nomogram that combined the prognostic signature was created for predicting the 1-, 3- and 5-year OS of LUAD. The accuracy of the nomogram prediction was evaluated using a calibration plot. Finally, cox regression analysis was applied to identify the prognostic value and clinical relationship of the signature in LUAD.
A total of 116 differentially expressed MRGs were detected in the TCGA dataset. We found that 12 MRGs were most significantly associated with OS by using the univariate regression analysis in LUAD. Then, multivariate Cox regression analyses were applied to construct the prognostic signature, which consisted of six MRGs-aldolase A (ALDOA), catalase (CAT), ectonucleoside triphosphate diphosphohydrolase-2 (ENTPD2), glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1), lactate dehydrogenase A (LDHA), and thymidylate synthetase (TYMS). The prognostic value of this signature was further successfully validated in the GSE31210 dataset. Furthermore, the calibration curve of the prognostic nomogram demonstrated good agreement between the predicted and observed survival rates for each of OS. Further analysis indicated that this signature could be an independent prognostic indicator after adjusting to other clinical factors. The high-risk group patients have higher levels of immune checkpoint molecules and are therefore more sensitive to immunotherapy. Finally, we confirmed six MRGs protein and mRNA expression in six lung cancer cell lines and firstly found that ENTPD2 might played an important role on LUAD cells colon formation and migration.
We established a prognostic signature based on MRGs for LUAD and validated the performance of the model, which may provide a promising tool for the diagnosis, individualized immuno-/chemotherapeutic strategies and prognosis in patients with LUAD.
鉴于代谢失调最近已被确定为癌症生物学的一个标志，本研究旨在建立并验证基于代谢相关基因（MRGs）的肺腺癌（LUAD）预后特征。
分别从癌症基因组图谱（TCGA）和分子特征数据库（MSigDB）获取具有临床信息的LUAD样本的基因测序数据和代谢相关基因集。通过Wilcoxon秩和检验鉴定差异表达的MRGs。然后，进行单变量cox回归分析以鉴定与总生存期（OS）相关的MRGs。通过多变量Cox回归分析建立预后特征。此外，在GSE31210数据集中验证该特征。此外，创建了一个结合预后特征的列线图，用于预测LUAD的1年、3年和5年OS。使用校准图评估列线图预测的准确性。最后，应用cox回归分析确定该特征在LUAD中的预后价值和临床关系。
在TCGA数据集中共检测到116个差异表达的MRGs。我们发现，通过在LUAD中进行单变量回归分析，有12个MRGs与OS最显著相关。然后，应用多变量Cox回归分析构建预后特征，该特征由六个MRGs组成，即醛缩酶A（ALDOA）、过氧化氢酶（CAT）、外核苷三磷酸二磷酸水解酶2（ENTPD2）、氨基葡萄糖磷酸N - 乙酰转移酶1（GNPNAT1）、乳酸脱氢酶A（LDHA）和胸苷酸合成酶（TYMS）。该特征的预后价值在GSE31210数据集中进一步得到成功验证。此外，预后列线图的校准曲线表明，每个OS的预测生存率与观察到的生存率之间具有良好的一致性。进一步分析表明，在调整其他临床因素后，该特征可能是一个独立预后指标。高危组患者的免疫检查点分子水平较高，因此对免疫治疗更敏感。最后，我们证实了六个MRGs在六种肺癌细胞系中的蛋白和mRNA表达，并首次发现ENTPD2可能在LUAD细胞的集落形成和迁移中起重要作用。
我们建立了基于MRGs的LUAD预后特征并验证了模型的性能，这可能为LUAD患者的诊断、个体化免疫/化疗策略及预后提供一个有前景的工具。
