The evolution of lung cancer and impact of subclonal selection in TRACERx.

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.

Salivary microbial dysbiosis may predict lung adenocarcinoma: A pilot study.

BACKGROUND: Adenocarcinoma is a more common type of Non-small cell lung cancer (NSCLC). Lung cancer showed a statistically significant increment in the Kamrup Urban district of Assam, Tripura, Sikkim, and Manipur of India. The goal of our pilot study is to identify non-invasive microbial biomarkers to detect lung adenocarcinoma (LAC). MATERIAL AND METHODS: DNA extraction from saliva samples of five LAC patients and five healthy controls was performed by Qiagen DNeasy blood and tissue kit using Lysozyme (3mg/ml) treatment. 16S rRNA genes of distinct regions (V3-V4) were amplified from saliva DNA by PCR. Paired-end sequencing targeting the V3-V4 region of the 16S rRNA gene has been performed on the Illumina MiSeq platform. Raw sequences were analyzed using the QIIME(Quantitative Insights Into Microbial Ecology) software package. RESULTS: Our preliminary results showed that Rothia mucilaginosa, Veillonella dispar, Prevotella melaninogenica, Prevotella pallens, Prevotella copri, Haemophilus parainfluenzae, Neisseria bacilliformis and Aggregatibacter segnis were significantly elevated in saliva of LAC which may serve as potential non-invasive biomarkers for LAC detection. Functional prediction analysis showed that bacterial genes involved in glycosyltransferase, peptidases, amino sugar, and nucleotide sugar metabolism, starch and sucrose metabolism were significantly enriched in LAC. CONCLUSION: These salivary bacteria may contribute to the development of LAC by increasing expression of glycosyltransferase and peptidases. However to understand their role in pathobiology, studies are required to perform in large cohort.

Smoking-associated upregulation of CBX3 suppresses ARHGAP24 expression to activate Rac1 signaling and promote tumor progression in lung adenocarcinoma.

Although tobacco smoking is a risk factor for lung adenocarcinoma (LUAD), the mechanisms by which tobacco smoking induces LUAD development remain elusive. Histone methylation levels in human bronchial epithelial cells have been reported to increase after exposure to cigarettes. In this study, we explored the mechanisms regulating histone methylation in LUAD in response to smoking. We found that the histone H3K9 methylation reader CBX3 was upregulated in current smokers with LUAD, and that CBX3 overexpression promoted LUAD progression. Functional enrichment analyses revealed that CBX3 regulated the activation of Rho GTPases in LUAD. We also found that by forming a complex with TRIM28, TRIM24, and RBBP4, CBX3 repressed the expression of ARHGAP24 and increased the amount of active Rac1 in LUAD cells. Collectively, these results suggest that smoking associated upregulation of CBX3 promotes LUAD progression by activating the ARHGAP24/Rac1 pathway. Hence, the CBX3/ARHGAP24/Rac1 axis may represent a promising therapeutic target in smoking-induced LUAD.

Tanshinone IIA suppresses the progression of lung adenocarcinoma through regulating CCNA2-CDK2 complex and AURKA/PLK1 pathway.

Lung adenocarcinoma (LUAD) belongs to a subgroup of non-small cell lung cancer (NSCLC) with an increasing incidence all over the world. Tanshinone IIA (TSA), an active compound of Salvia miltiorrhiza Bunge., has been found to have anti-tumor effects on many tumors, but its anti-LUAD effect and its mechanism have not been reported yet. In this study, bio-information analysis was applied to characterize the potential mechanism of TSA on LUA, biological experiments were used to verify the mechanisms involved. TCGA, Pubchem, SwissTargetPrediction, Venny2.1.0, STRING, DAVID, Cytoscape 3.7.2, Omicshare, GEPIA, RSCBPDB, Chem Draw, AutoDockTools, and PyMOL were utilized for analysis in the bio-information analysis and network pharmacology. Our experiments in vitro focused on the anti-LUAD effects and mechanisms of TSA on LUAD cells (A549 and NCI-H1975 cells) via MTT, plate cloning, Annexin V-FITC and PI dual staining, flow cytometry, and western blot assays. A total of 64 differentially expressed genes (DEGs) of TSA for treatment of LUAD were screened out. Gene ontology and pathway analysis revealed characteristic of the DEGs network. After GEPIA-based DEGs confirmation, 46 genes were considered having significant differences. Further, 10 key DEGs (BTK, HSD11B1, ADAM33, TNNC1, THRA, CCNA2, AURKA, MIF, PLK1, and SORD) were identified as the most likely relevant genes from overall survival analysis. Molecular Docking results showed that CCNA2, CDK2 and PLK1 had the lowest docking energy. MTT and plate cloning assays results showed that TSA inhibited the proliferation of LUAD cells in a concentration-dependent manner. Annexin V-FITC and PI dual staining and flow cytometry assays results told that TSA promoted the apoptosis of the two LUAD cells in different degrees, and induced cycle arrest in the G1/S phase. Western blot results showed that TSA significantly down-regulated the expression of CCNA2, CDK2, AURKA, PLK1, and p-ERK. In summary, TSA could suppress the progression of LUAD by inducing cell apoptosis and arresting cell cycle, and these were done by regulating CCNA2-CDK2 complex and AURKA/PLK1 pathway. These findings are the first to demonstrate the molecular mechanism of TSA in treatment of LUAD combination of network bio-information analysis and biological experiments in vitro.

Protumor Effects of Histone H3-H4 Chaperone Antisilencing Feature 1B Gene on Lung Adenocarcinoma: In Silico and In Vitro Analyses.

BACKGROUND: ASF1B is a member of the histone H3-H4 chaperone antisilencing feature 1 (ASF1). ASF1B reportedly acts as an oncogene in several cancers including, breast cancer and cervical cancer. To date, the role of ASF1B in lung adenocarcinoma (LUAD) is not elucidated. METHODS: The TCGA database, containing data for 33 cancer types, was used to explore the dysregulation and prognostic value of the ASF1B gene in pan-cancer data. R software packages and public databases/webservers were applied for bioinformatics and statistical analyses. Using in vitro models, immunoprecipitation and immunofluorescence were utilized to investigate if BCAR1 interacted with ASF1B in LUAD. Further, transfection experiments were performed to validate the expression pattern of ASF1B in LUAD and examine its regulating role in tumor-associated processes including tumor cell proliferation and migration. RESULTS: ASF1B was found to be significantly elevated in LUAD and the majority of cancer types, except PCPG (pheochromocytoma and paraganglioma). The overexpression of ASF1B was associated with worse prognostic outcomes in most cancer types including LUAD. ASF1B was associated with lymph node metastasis, and in vitro, it promoted the proliferation and migration of LUAD cells. ASF1B knockdown suppressed LUAD cell proliferation and migration and also diminished the expression of cell cycle, metastasis, and EMT signaling-associated proteins. BCAR1 was found positively correlated and interacting with ASF1B, and BCAR1 overexpression reversed the effects of ASF1B knockdown in LUAD cells. CONCLUSION: These findings indicated that ASF1B plays a significant role in the tumor progression of LUAD and BCAR1 mediates the tumor-promotive effects of ASF1B, acting as an intermediate protein. Therefore, the ASF1B/BCAR1 axis might be regarded as a putative therapeutic target for LUAD.

TGFß Signaling Activated by Cancer-Associated Fibroblasts Determines the Histological Signature of Lung Adenocarcinoma.

Invasive lung adenocarcinoma (LADC) can be classified histologically as lepidic, acinar, papillary, micropapillary, or solid. Most LADC tumors manifest several of these histological subtypes, with heterogeneity being related to therapeutic resistance. We report here that in immunodeficient mice, human LADC cells form tumors with distinct histological features, MUC5AC-expressing solid-type or cytokeratin 7 (CK7)-expressing acinar-type tumors, depending on the site of development, and that a solid-to-acinar transition (SAT) could be induced by the tumor microenvironment. The TGFß-Smad signaling pathway was activated in both tumor and stromal cells of acinar-type tumors. Immortalized cancer-associated fibroblasts (CAF) derived from acinar-type tumors induced SAT in 3D cocultures with LADC cells. Exogenous TGFß1 or overexpression of an active form of TGFß1 increased CK7 expression and reduced MUC5AC expression in LADC cells, and knockdown of Tgfb1 mRNA in CAFs attenuated SAT induction. RNA-sequencing analysis suggested that angiogenesis and neutrophil recruitment are associated with SAT in vivo. Our data indicate that CAF-mediated paracrine TGFß signaling induces remodeling of tumor tissue and determines the histological pattern of LADC, thereby contributing to tumor heterogeneity. SIGNIFICANCE: CAFs secrete TGFß to induce a solid-to-acinar transition in lung cancer cells, demonstrating how the tumor microenvironment influences histological patterns and tumor heterogeneity in lung adenocarcinoma.

LINC01089 suppresses lung adenocarcinoma cell proliferation and migration via miR-301b-3p/STARD13 axis.

BACKGROUND: Lung adenocarcinoma (LUAD) is one of the most common cancers with high morbidity and mortality worldwide. Long non-coding RNAs (lncRNAs) serve as tumor promoters or suppressors in the development of various human malignancies, including LUAD. Although long intergenic non-protein coding RNA 1089 (LINC01089) suppresses the progression of breast cancer, its mechanism in LUAD requires further exploration. Thus, we aimed to investigate the underlying function and mechanism of LINC01089 in LUAD. METHODS: The expression of LINC01089 in LUAD and normal cell lines was detected. Functional assays were applied to measure cell proliferation, apoptosis and migration. Besides, mechanism experiments were employed for assessing the interplay among LINC01089, miR-301b-3p and StAR related lipid transfer domain containing 13 (STARD13). Data achieved in this study was statistically analyzed with Student's t test or one-way analysis of variance. RESULTS: LINC01089 expression was significantly down-regulated in LUAD tissues and cells and its overexpression could reduce cell proliferation and migration. Moreover, LINC01089 could regulate STARD13 expression through competitively binding to miR-301b-3p in LUAD. Additionally, rescue assays uncovered that STARD13 depletion or miR-301b-3p overexpression could countervail the restraining effect of LINC01089 knockdown on the phenotypes of LUAD cells. CONCLUSION: LINC01089 served as a tumor-inhibitor in LUAD by targeting miR-301b-3p/STARD13 axis, providing an innovative insight into LUAD therapies. Trial registration Not applicable.

Aggressive early-stage lung adenocarcinoma is characterized by epithelial cell plasticity with acquirement of stem-like traits and immune evasion phenotype.

Lung adenocarcinoma (LUAD) is the main non-small-cell lung cancer diagnosed in ~40-50% of all lung cancer cases. Despite the improvements in early detection and personalized medicine, even a sizable fraction of patients with early-stage LUAD would experience disease relapses and adverse prognosis. Previous reports indicated the existence of LUAD molecular subtypes characterized by specific gene expression and mutational profiles, and correlating with prognosis. However, the biological and molecular features of such subtypes have not been further explored. Consequently, the mechanisms driving the emergence of aggressive LUAD remained unclear. Here, we adopted a multi-tiered approach ranging from molecular to functional characterization of LUAD and used it on multiple cohorts of patients (for a total of 1227 patients) and LUAD cell lines. We investigated the tumor transcriptome and the mutational and immune gene expression profiles, and we used LUAD cell lines for cancer cell phenotypic screening. We found that loss of lung cell lineage and gain of stem cell-like characteristics, along with mutator and immune evasion phenotypes, explain the aggressive behavior of a specific subset of lung adenocarcinoma that we called C1-LUAD, including early-stage disease. This subset can be identified using a 10-gene prognostic signature. Poor prognosis patients appear to have this specific molecular lung adenocarcinoma subtype which is characterized by peculiar molecular and biological features. Our data support the hypothesis that transformed lung stem/progenitor cells and/or reprogrammed epithelial cells with CSC characteristics are hallmarks of this aggressive disease. Such discoveries suggest alternative, more aggressive, therapeutic strategies for early-stage C1-LUAD.

Emergency rigid bronchoscopy and immunotherapy: successful combination in dramatic respiratory debut of pulmonary adenocarcinoma.

Malignant central airway obstruction is a life-threatening condition that often causes respiratory failure. In many cases, treatment of tumor in rigid bronchoscopy must be performed urgently, soothing respiratory symptoms and improving patient quality of life, in many cases reducing time to and allowing application of oncologic therapies. Immuno-oncologic therapies target the immune system selectively and are therefore much less toxic than standard chemotherapies, sometimes leading to outstanding results in advanced cancers for which there were no effective treatments until a few years ago. This report shows the effect of the joint application of rigid bronchoscopy and targeted immunotherapy in an emergency scenario, resulting in an unexpected extraordinary therapeutic success.

Response to pembrolizumab in a patient with primary lung adenocarcinoma originated from indium lung.

BACKGROUND: Indium is a metal used as a compound called indium-tin oxide for liquid crystal display. Its inhalation causes lung toxicity, resulting in a new occupational lung disease called indium lung. Although the carcinogenicity of indium has been reported in an animal model, its carcinogenicity in humans is unknown. CASE PRESENTATION: This is the first reported case of a primary lung cancer originating from indium lung. In this report, we describe a 46-year-old man with interstitial pneumonia-type indium lung diagnosed 16 years ago. The initial symptom was left chest pain, and computed tomography showed a mass adjacent to the aorta with left pleural effusion. Specimens collected using video-assisted thoracoscopy revealed an adenocarcinoma with a high expression of programmed cell death-ligand 1 (cT4N0M1a stage IVA). Although the lesions showed a remarkable aggressive nature, the patient benefited from pembrolizumab, a monoclonal antibody against programmed cell death 1, which was used as second-line therapy for 2 years. CONCLUSIONS: It is important for clinicians to be aware of lung cancer development in indium-exposed workers or in patients with indium lung, as this could have an aggressive behavior. Treatment with immune checkpoint inhibitors is an option even in patients with interstitial pneumonia-type indium lung.

Novel Histologic Classification of Small Tumor Cell Nests for Lung Adenocarcinoma With Prognostic and Etiological Significance: Small Solid Nests and Pure Micropapillary Nests.

Small tumor cell nests such as micropapillary nests are histologic poor prognostic markers for adenocarcinomas of various organs, including the lung. However, for the lung, the association of micropapillary patterns with smoking is controversial, which may be because of a vague definition of micropapillary patterns. This study clarifies the implications of small tumor cell nests by introducing a new dichotomic classification based on the glandular polarity of tumor cells: pure micropapillary nests (pMPs), preserving glandular polarity, and small solid nests (SSNs), lacking polarity. We examined the clinicopathologic factors in 436 resected adenocarcinomas, and analyzed the overall survival between groups classified by either the presence or absence of pMPs and SSNs. pMP was positively associated with nonsmoking-related features such as epidermal growth factor receptor mutations and thyroid transcription factor 1 expression. By contrast, SSN was positively associated with smoking-related features such as KRAS mutations and hepatocyte nuclear factor-4a expressions. Besides, pMP and SSN were significant and independent indicators of poor prognosis in all stages. SSN was an indicator in stage I too, whereas pMP was not. Furthermore, prognoses of the group with SSN were significantly worse than those of pMP-only group. In conclusion, the present study has revealed 2 completely different patterns of small tumor cell nests in lung adenocarcinoma, the nonsmoking-related pMPs, and the smoking-related SSNs, by considering glandular polarity. MPP should include only pMPs, and SSNs should be in a solid pattern. This novel classification might boast clinical significance as a potent poor prognostic marker as well as a factor reflecting etiological and genetic characters.

Pan-cancer investigation reveals mechanistic insights of planar cell polarity gene Fuz in carcinogenesis.

The fuzzy planar cell polarity protein (Fuz) is an effector component of the planar cell polarity (PCP) signaling. Together with other core and effector proteins, the PCP pathway controls polarized cell movements. Fuz was also reported as a negative regulator of cell survival. In this study, we performed a pan-cancer survey to demonstrate the role of Fuz in multiple types of cancer. In head-neck squamous cell carcinoma and lung adenocarcinoma tumor samples, a reduction of Fuz transcript expression was detected. This coincides with the poor overall survival probabilities of these patients. We further showed that Fuz promoter hypermethylation contributes to its transcriptional downregulation. Meanwhile, we also identified a relatively higher mutation frequency at the 404th arginine amino acid residue in the coding sequence of Fuz locus, and further demonstrated that mutant Fuz proteins perturb the pro-apoptotic function of Fuz. In summary, our study unveiled an intriguing relationship between Fuz dysregulation and cancer prognosis, and further provides mechanistic insights of Fuz's involvement in carcinogenesis.

The Efficacy of First-Generation EGFR-TKI Combined With Brain Radiotherapy as the First-Line Treatment for Lung Adenocarcinoma Patients With Brain Metastases and EGFR Sensitive Mutations: A Retrospective study.

BACKGROUND: It was controversial that whether LUAD patients with brain metastases (BMs) and EGFR sensitive mutations should be conducted using brain radiotherapy when treated with first-generation EGFR-TKI. Herein, a retrospective study was designed to compare the efficacy of first-generation EGFR-TKI combined with brain radiotherapy and EGFR-TKI alone as first-line treatment for these LUAD patients. PATIENTS AND METHODS: We retrospectively analyzed the status of patients with advanced LUAD carrying EGFR sensitive mutations who received first-generation EGFR-TKI treatment in our center. iPFS was the first time of intracranial progression or death from the diagnosis of BMs, PFS was the time of progression of any site or death from the diagnosis of BMs, and OS was the time of confirmed BMs to death or the last follow-up time. Differences in characteristics between groups were compared using the Chi-square test. The Kaplan-Meier method was used to calculate the iPFS, PFS, and OS. Univariate analysis, multivariate analysis, and subgroup analysis were conducted by Cox regression model. RESULTS: There were 77 patients (77/134, 57.5%) in the TKI + RT group and 57 patients (57/134, 42.5%) in the TKI group. TKI + RT group had a significant higher intracranial ORR and DCR, and the combination therapy was independently significantly associated with a longer iPFS (18.9 vs. 10.5 months, P = 0.0009), systematic PFS (12.5 vs. 8.4 months, P = 0.0071) and OS (30.8 vs. 22.7 months, P = 0.0183). Females, non-smokers, and younger patients benefited more from the combination therapy. Subgroup analysis demonstrated that the combination therapy could improve the iPFS in patients with more than 3 BMs (P = 0.005); however, it couldn't improve the OS for these patients. CONCLUSION: Our study confirmed the effect of the combination of EGFR-TKI and brain radiotherapy as first-line treatment for LUAD patients with BMs and EGFR sensitive mutations.

Potential role of glucosamine-phosphate N-acetyltransferase 1 in the development of lung adenocarcinoma.

Glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is a key enzyme associated with glucose metabolism and uridine diphosphate-N-acetylglucosamine biosynthesis. Abnormal GNPNAT1 expression might be associated with carcinogenesis. We analyzed multiple lung adenocarcinoma (LUAD) gene expression databases and verified GNPNAT1 higher expression in LUAD tumor tissues than in normal tissues. Moreover, we analyzed the survival relationship between LUAD patients' clinical status and GNPNAT1 expression, and found higher GNPNAT1 expression in LUAD patients with unfavorable prognosis. We built GNPNAT1 gene co-expression networks and further annotated the co-expressed genes' Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and various associated regulatory factors. These co-expression genes' functional networks mainly participate in chromosome segregation, RNA metabolic process, and RNA transport. We analyzed GNPNAT1 genetic alterations and co-occurrence networks, and the functional networks of these genes showed that GNPNAT1 participates in multiple steps of cell cycle transition and in the development of some cancers. We assessed the correlation between GNPNAT1 expression and cancer immune infiltrates and showed that GNPNAT1 expression is correlated with several immune cells, chemokines, and immunomodulators in LUAD. We found that GNPNAT1 correlates with LUAD development and prognosis, laying a foundation for further research, especially in immunotherapy.

Preliminary Investigation and Imaging Analysis of Early Lung Cancer Screening Among Petroleum Workers in North China.

BACKGROUND: The detection rate of lung nodules has increased significantly among petroleum workers in North China since the low-dose CT (LDCT) screening has been widely carried out. What's more, the number of confirmed early lung cancers is increasing continuously. Therefore, a great deal of concern for the high risk of lung cancer has been shown among petroleum workers. PURPOSE: To improve the screening efficiency and maximize the benefits of the subjects, the current situation of LDCT lung cancer screening should be understood and the imaging characteristics of early lung cancer should be analyzed for petroleum workers in North China. MATERIALS AND METHODS: Firstly, the dynamic changes of LDCT early lung cancer screening for petroleum workers in North China were analyzed in recent years. Then, the survey data of 3121 petroleum workers was compared with that of 1868 non-petroleum workers, which was analyzed. Finally, 91 patients (129 nodular lung cancer) confirmed by pathology were retrospectively analyzed, and the data of which was compared with the clinical features obtained from survey data above. The imaging characteristics and related factors of different subtypes of lung adenocarcinoma were discussed and analyzed. RESULTS: Lung nodules were found in 810 cases (25.95%) out of 3121 petroleum workers; and the surgery was chosen by 42 patients, 38 of whom were confirmed as lung cancer. Compared with the data of screened petroleum workers, there were more older people and more females as well as a higher proportion of people with family malignancy history, and a lower proportion of smoking people in 91 patients with lung cancer. As the pathological grade of tumor nodules increased, the volume and diameter of nodules gradually increased, and the mean density, maximum density and standard deviation of density also increased (p < 0.001). The volume and diameter of nodules were positively correlated with ages (p < 0.05). CONCLUSION: The occurrence of lung adenocarcinoma is closely related to the family history of malignant tumors, and the constituent ratio of young women without a history of smoking increased significantly. At the same time, the quantitative information obtained by using CT images has important value in predicting its pathological subtypes.

Chromobox 4 facilitates tumorigenesis of lung adenocarcinoma through the Wnt/ß-catenin pathway.

Chromobox 4 (CBX4) is a core component of polycomb-repressive complex 1 with important roles in cancer biology and tissue homeostasis. Aberrant expression of CBX4 has been implicated in several human malignancies. However, its role and underlying mechanisms in the tumorigenesis of lung adenocarcinoma (LUAD) have not been defined in vivo. Here, we found that expression of CBX4 was frequently up-regulated in human LUAD samples and correlated with poor patient survival. Importantly, genetic ablation of CBX4 greatly dampened lung tumor formation and improved survival in the KrasG12D/P53L/L (KP) autochthonous mouse model of LUAD. In addition, CBX4 depletion significantly inhibited proliferation and anchorage-independent growth of KP mouse embryonic fibroblasts. Moreover, ectopic CBX4 expression clearly promoted proliferation and anchorage-independent growth in both human and mouse LUAD cells, whereas silencing of CBX4 exerted opposite effects. Mechanistically, CBX4 promoted growth of LUAD cells through activation of the Wnt/ß-catenin pathway. Furthermore, expression levels of CBX4 were positively correlated with ß-catenin in human LUAD samples. In conclusion, our data suggest that CBX4 plays an oncogenic role via the Wnt/ß-catenin pathway and could serve as a potential therapeutic target in LUAD.

The Lung Adenocarcinoma Microenvironment Mining and Its Prognostic Merit.

BACKGROUND: As a common pathological type of lung cancer, lung adenocarcinoma (LUAD) is mainly treated by surgery, chemotherapy, targeted therapy and radiotherapy. Although a relatively mature treatment system has been established, there are few studies on the microenvironment of LUAD. MATERIAL AND METHODS: The immune and stromal scores of patients from the LUAD cohort in the TCGA database were obtained by using ESTIMATE. The relationship of immune and stromal scores with the clinicopathological characteristics and overall survival of LUAD patients was assessed by R. GO, KEGG and Cox regression analyses were employed to analyze intersecting genes and to identify reliable prognostic markers. The identified genes were also analyzed in the GEPIA database to assess their correlations with survival, and these relationships were verified with the Kaplan-Meier Plotter database. RESULTS: The immune score was related to the survival time and tumor topography of LUAD patients. There was a significant correlation between stromal score and tumor metastasis. Through multivariate analysis, stage (HR = 1.640, 95% CI = 1.019-2.642, P = 0.042) and risk score (HR = 1.036, 95% CI = 1.026-1.046, P < 0.001). The genes (ARHGAP15, BTLA, CASS4, CLECL1, FAM129C, STAP1, TESPA1, and S100P) showed credible prognostic value in LUAD patients in TCGA through GEPIA database online analysis and verification in the Kaplan-Meier plotter database. CONCLUSIONS: In the microenvironment of lung adenocarcinoma, the differentially expressed genes screened by immune score and stromal score have certain value in evaluating the survival/prognosis of patients, as well as the invasion and progression of tumors.

Comprehensive molecular analyses of a TNF family-based signature with regard to prognosis, immune features, and biomarkers for immunotherapy in lung adenocarcinoma.

BACKGROUND: Tumour Necrosis Factor (TNF) family members play important roles in mounting anti-tumour immune responses, and clinical trials targeting these molecules are ongoing. However, the expression patterns and clinical significance of TNF members in lung adenocarcinoma (LUAD) remain unrevealed. This study aimed to explore the gene expression profiles of TNF family members in LUAD and constructed a TNF family-based prognosis signature. METHODS: In total, 1300 LUAD cases from seven different cohorts were collected. Samples from The Cancer Genome Atlas (TCGA) were used as the training set, and the RNA data from five Gene Expression Omnibus (GEO) datasets and qPCR data from 102 samples were used for validation. The immune profiles and potential immunotherapy response prediction value of the signature were also explored. FINDINGS: After univariate Cox proportional hazards regression and stepwise multivariable Cox analysis, a TNF family-based signature was constructed in the TCGA dataset that significantly stratified cases into high- and low-risk groups in terms of OS. This signature remained an independent prognostic factor in multivariate analyses. Moreover, the clinical significance of the signature was well validated in different clinical subgroups and independent validation cohorts. Further analysis revealed that signature high-risk patients were characterized by distinctive immune cell proportions and immune-suppressive states. Additionally, signature scores were positively related to multiple immunotherapy biomarkers. INTERPRETATION: This was the first TNF family-based model for predicting outcomes and immune landscapes for patients with LUAD. The capability of this signature for predicting immunotherapy response needs further validation.