Identification of candidate genes and prognostic value analysis in patients with PDL1-positive and PDL1-negative lung adenocarcinoma
PDL1-positive 和 PDL1-negative 肺腺癌候选基因的筛选及预后价值分析
- 作者列表："Xiaoguang Qi","Chunyan Qi","Xindan Kang","Yi Hu","Weidong Han
Background 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. Methods 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. Results 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 BRCA1, 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. Conclusions 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.
背景越来越多的证据表明，靶向程序性细胞死亡蛋白 1 (PD-1) 单克隆抗体是一种很有前途的肺腺癌免疫治疗方法。尽管 pd1 受体配体 1 (PDL1) 的表达被广泛认为是 anti-PD-1 治疗最强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，我们进行这项研究是为了探索差异表达基因 (DEGs)，阐明 PDL1 在肺腺癌中的调控机制。方法从 Gene Expression Omnibus (GEO) 数据库中获得 GSE99995 数据集。将 PDL1 表达的患者分为 PDL1-positive 组和 PDL1-negative 组。使用 R 筛选 DEGs。使用该数据库对 Gene Ontology (GO) 数据库和京都基因和基因组百科全书 (KEGG) 进行了分析，用于注释、可视化和整合发现。使用 Cytoscape 可视化 DEGs 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。使用涉及基因表达谱交互分析的生存分析来验证 GEO 结果。在癌症基因组图谱 (TCGA) 数据库中 5 个数据集的联合研究中进一步分析了 hub 基因的突变特征。结果共检出 869 例 DEGs，PDL1-positive 组 387 例，PDL1-negative 组 482 例。PDL1-positive 组 GO 和 KEGG 分析结果主要表现为细胞黏附相关的生物学过程和通路的富集以及过氧化物酶体增殖物激活受体 (PPAR) 信号通路,而与细胞分裂和修复相关的生物学过程和途径主要富集在 PDL1-negative 组。PPI 网络分析期间筛选了前 10 个 hub 基因。值得注意的是，生存分析显示 BRCA1 主要参与细胞周期和 DNA 损伤反应，是肺腺癌的一个新的预后指标。此外，不同形式肺腺癌患者的预后与潜在枢纽基因的突变和通路差异相关。结论 PDL1-positive 肺腺癌和 PDL1-negative 肺腺癌可能是肺腺癌的不同亚型。Hub 基因可能在 PDL1 调控通路中发挥重要作用。需要对 hub 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治疗至关重要。
METHODS:BACKGROUND:The objectives of this study are to assess the chest drainage volumes of patients undergoing anatomic resection of non-small cell lung carcinoma and to determine the safety and effectiveness of administering enoxaparin for thromboprophylaxis. METHODS:A total of 77 patients were included in the study. A study was conducted on the first group of 42 patients in which enoxaparin prophylaxis (enoxaparin, 40 mg) was subcutaneously injected once a day for a period of three days after the patients underwent anatomic pulmonary resection between March 2016 and March 2018. An enoxaparin-free group was identified and included 35 patients who received no enoxaparin prophylaxis after undergoing anatomic pulmonary resection between February 2013 and February 2016. We compared the changes in hemoglobin (Hb) levels, postoperative 3-day drainage volume, transfusion volume, pulmonary complications and length of stay between the two groups. RESULTS:No differences in postoperative Hb levels, chest drainage volume, transfusion volume, postoperative complications, and length of stay were observed between the two groups. Deep-vein thrombosis was noted in a patient in the enoxaparin-free group. No major bleeding was noted in either group. CONCLUSION:We found that for patients undergoing anatomic resection of primary lung cancer, the blood transfusion and chest drainage volumes did not differ, regardless of whether the patients were given enoxaparin. To the best of our knowledge, the impact of low-molecular-weight heparin on chest tube drainage volume for patients undergoing anatomic resection of non-small cell lung carcinoma has not been investigated before.
METHODS::The aim of the present study was to compare the safety and efficacy of cryoablation (CA) and microwave ablation (MWA) as treatments for non-small cell lung cancer (NSCLC). Patients with stage IIIB or IV NSCLC treated with CA (n=45) or MWA (n=56) were enrolled in the present study. The primary endpoint was progression-free survival (PFS); the secondary endpoints included overall survival (OS) time and adverse events (AEs). The median PFS times between the two groups were not significantly different (P=0.36): CA, 10 months [95% confidence interval (CI), 7.5-12.4] vs. MWA, 11 months (95% CI, 9.5-12.4). The OS times between the two groups were also not significantly different (P=0.07): CA, 27.5 months (95% CI, 22.8-31.2 months) vs. MWA, 18 months (95% CI, 12.5-23.5). For larger tumors (>3 cm), patients treated with MWA had significantly longer median PFS (P=0.04; MWA, 10.5 months vs. CA, 7.0 months) and OS times (P=0.04; MWA, 24.5 months vs. CA, 14.5 months) compared patients treated with CA. However, for smaller tumors (≤3 cm), median PFS (P=0.79; MWA, 11.0 months vs. CA, 13.0 months) and OS times (P=0.39; MWA, 30.0 months vs. CA, 26.5 months) between the two groups did not differ significantly. The incidence rates of AEs were similar in the two groups (P>0.05). The number of applicators, tumor size and length of the lung traversed by applicators were associated with a higher risk of pneumothorax and intra-pulmonary hemorrhage in the two groups. Treatment with CA resulted in significantly less intraprocedural pain compared with treatment with MWA (P=0.001). Overall, the present study demonstrated that CA and MWA were comparably safe and effective procedures for the treatment of small tumors. However, treatment with MWA was superior compared with CA for the treatment of large tumors.
METHODS:BACKGROUND:BRAF mutations occurring in 1%-5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort. PATIENTS AND METHODS:Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS). RESULTS:Of the 118 patients enrolled, 101 presented with a BRAFV600 mutation and 17 with BRAFnonV600 mutations; the median follow-up was 23.9 months. In the BRAFnonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAFV600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%-54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8-6.8), and OS was 10 months (95% CI 6.8-15.7). The vemurafenib safety profile was consistent with previous publications. CONCLUSION:Routine biomarker screening of NSCLC should include BRAFV600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAFV600-mutated NSCLC but not those with BRAFnonV600 mutations. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT02304809.