Qi Xiaoguang, Qi Chunyan, Kang Xindan, Hu Yi, Han Weidong
Department of Oncology, Chinese PLA General Hospital, Beijing, China.
Department of Special Ward, Chinese PLA General Hospital, Beijing, China.
PeerJ. 2020 Jun 17;8:e9362. doi: 10.7717/peerj.9362. eCollection 2020.
Increasing bodies of evidence reveal that targeting a programmed cell death protein 1 (PD-1) monoclonal antibody is a promising immunotherapy for lung adenocarcinoma. Although PD receptor ligand 1 (PDL1) expression is widely recognized as the most powerful predictive biomarker for anti-PD-1 therapy, its regulatory mechanisms in lung adenocarcinoma remain unclear. Therefore, we conducted this study to explore differentially expressed genes (DEGs) and elucidate the regulatory mechanism of PDL1 in lung adenocarcinoma.
The GSE99995 data set was obtained from the Gene Expression Omnibus (GEO) database. Patients with and without PDL1 expression were divided into PDL1-positive and PDL1-negative groups, respectively. DEGs were screened using R. The Gene Ontology (GO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) were analyzed using the Database for Annotation, Visualization and Integrated Discovery. Protein-protein interaction (PPI) networks of DEGs was visualized using Cytoscape, and the MNC algorithm was applied to screen hub genes. A survival analysis involving Gene Expression Profiling Interactive Analysis was used to verify the GEO results. Mutation characteristics of the hub genes were further analyzed in a combined study of five datasets in The Cancer Genome Atlas (TCGA) database.
In total, 869 DEGs were identified, 387 in the PDL1-positive group and 482 in the PDL1-negative group. GO and KEGG analysis results of the PDL1-positive group mainly exhibited enrichment of biological processes and pathways related to cell adhesion and the peroxisome proliferators-activated receptors (PPAR) signaling pathway, whereas biological process and pathways associated with cell division and repair were mainly enriched in the PDL1-negative group. The top 10 hub genes were screened during the PPI network analysis. Notably, survival analysis revealed , mainly involved in cell cycle and DNA damage responses, to be a novel prognostic indicator in lung adenocarcinoma. Moreover, the prognosis of patients with different forms of lung adenocarcinoma was associated with differences in mutations and pathways in potential hub genes.
PDL1-positive lung adenocarcinoma and PDL1-negative lung adenocarcinoma might be different subtypes of lung adenocarcinoma. The hub genes might play an important role in PDL1 regulatory pathways. Further studies on hub genes are warranted to reveal new mechanisms underlying the regulation of PDL1 expression. These results are crucial for understanding and applying precision immunotherapy for lung adenocarcinoma.
越来越多的证据表明，靶向程序性细胞死亡蛋白1（PD-1）单克隆抗体是一种有前景的肺腺癌免疫疗法。尽管PD受体配体1（PDL1）表达被广泛认为是抗PD-1治疗最有力的预测生物标志物，但其在肺腺癌中的调控机制仍不清楚。因此，我们开展本研究以探索差异表达基因（DEG）并阐明PDL1在肺腺癌中的调控机制。
从基因表达综合数据库（GEO）获取GSE99995数据集。有和无PDL1表达的患者分别分为PDL1阳性组和PDL1阴性组。使用R软件筛选DEG。利用注释、可视化与集成发现数据库对基因本体论（GO）数据库和京都基因与基因组百科全书（KEGG）进行分析。使用Cytoscape可视化DEG的蛋白质-蛋白质相互作用（PPI）网络，并应用MNC算法筛选枢纽基因。使用基因表达谱交互分析进行生存分析以验证GEO结果。在癌症基因组图谱（TCGA）数据库的五个数据集的联合研究中进一步分析枢纽基因的突变特征。
共鉴定出869个DEG，PDL1阳性组中有387个，PDL1阴性组中有482个。PDL1阳性组的GO和KEGG分析结果主要显示与细胞黏附及过氧化物酶体增殖物激活受体（PPAR）信号通路相关的生物学过程和途径富集，而与细胞分裂和修复相关的生物学过程和途径主要在PDL1阴性组中富集。在PPI网络分析过程中筛选出前10个枢纽基因。值得注意的是，生存分析显示，主要参与细胞周期和DNA损伤反应，是肺腺癌中的一种新型预后指标。此外，不同类型肺腺癌患者的预后与潜在枢纽基因的突变和途径差异相关。
PDL1阳性肺腺癌和PDL1阴性肺腺癌可能是肺腺癌的不同亚型。枢纽基因可能在PDL1调控途径中起重要作用。有必要对枢纽基因进行进一步研究以揭示PDL1表达调控的新机制。这些结果对于理解和应用肺腺癌的精准免疫疗法至关重要。
