Search

Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC) and is characterized by its heterogeneity and poor prognosis. The role of ribosomal proteins RPLP0, RPLP1 and RPLP2 in multiple cancers has been implicated. However, their function in LUAD and their correlation with the poor prognosis of LUAD remains elusive. In this study, we performed a comprehensive bioinformatic analysis of the impact of these ribosomal proteins on LUAD. Our findings reveal that RPLP0, RPLP1 and RPLP2 are overexpressed in LUAD, which are likely attributed to abnormal copy number variations and decreased methylation levels of their promoters. LUAD patients with high expression of RPLP0, RPLP1 or RPLP2 have worse clinical outcomes in terms of overall survival (OS), first progression (FP) and post-progression survival (PPS), indicating poor prognosis. Moreover, the expression of RPLP0, RPLP1 and RPLP2 affects immune cell infiltration in LUAD tissues. Finally, we identified multiple existing drugs that may inhibit the expression of RPLP1 and RPLP2. Collectively, our data implicate the oncogenic role of RPLP0, RPLP1 and RPLP2 in LUAD and underscore their prognostic value in LUAD patients., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Non-small cell lung cancer (NSCLC) is histologically classified into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LSCC). However, some tumors are histologically ambiguous and other pathophysiological features or microenvironmental factors may be more prominent. Here we report integrative multiomics analyses using data for 229 patients from a Korean NSCLC cohort and 462 patients from previous multiomics studies. Histological examination reveals five molecular subtypes, one of which is a NSCLC subtype with PI3K-Akt pathway upregulation, showing a high proportion of metastasis and poor survival outcomes regardless of any specific NSCLC histology. Proliferative subtypes are present in LUAD and LSCC, which show strong associations with whole genome doubling (WGD) events. Comprehensive characterization of the immune microenvironment reveals various immune cell compositions and neoantigen loads across molecular subtypes, which predicting different prognoses. Immunological subtypes exhibit a hot tumor-enriched state and a higher efficacy of adjuvant therapy., Competing Interests: Competing interests: Kwang Pyo Kim is the CEO of NioBiopharmaceuticals, Inc. Se Jin Jang is the chief technology officer of SG Medical, Inc. All other authors declare no competing interests., (© 2024. The Author(s).)

Background: This study aimed to evaluate the prognostic value of the newly revised International Association for the Study of Lung Cancer (IASLC) grading system (2020) on the 5-year overall survival (OS) and recurrence-free survival (RFS) in patients with lung adenocarcinoma (LADC)., Methods: Clinical studies that investigated the prognostic value of revised IASLC staging system in patients with LADC were retrieved from the PubMed, Web of Science, ScienceDirect, and Cochrane Library databases. This study was conducted in accordance to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklists., Results: Based on inclusion and exclusion criteria, we included 12 studies for analysis. The grade of LADC was assessed by revised IASLC system, which included three grades. Compared to Grade 3 LADC, grade 1 (total [95% CI]: 1.38 [1.19, 1.60]) and grade 2 (total [95% CI]: 1.29 [1.15, 1.44]) LADC had higher 5-year OS rates. Similarly, Grade 1 (total [95% CI]: 1.76 [1.42, 2.18]) and Grade 2 (total [95% CI]: 1.51 [1.28, 1.77]) had higher 5-year RFS rates Grade 3 LADC. However, 5-year OS and RFS had no significant difference between Grade 1 and Grade 2 patients., Conclusion: This systematic review and meta-analysis provides evidence that the newly revised IASLC grading system is significantly associated with the prognosis of patients with LADC, where Grade 3 indicated unfavorable prognosis., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of The First People’s Hospital of Jiande. Written informed consent was obtained from all the participants. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Long non-coding RNAs (lncRNAs) have a notable role in the diagnosis and prognosis of cancer. However, the associations between lncRNA-related hub genes (LRHGs) expression and the corresponding outcomes have not been fully understood in lung adenocarcinoma (LUAD). Here, a total of 71 patients diagnosed with LUAD and 60 healthy volunteers at The First Affiliated Hospital of Huzhou University from April, 2023 to December, 2023 were enrolled in the present study. A LRHGs model was established using least absolute shrinkage and selection operator analyses of The Cancer Genome Atlas-LUAD datasets. The underlying mechanisms of the LRHGs were investigated via Gene Set Enrichment Analysis and Gene Set Variation Analysis. Additionally, the diagnostic role of serum HOXD cluster antisense RNA 2 (HOXD-AS2) was assessed by receiver operating characteristic (ROC) curve analysis. Lastly, TCGA-LUAD samples were divided into high- and low-HOXD-AS2 expression groups based on the median expression. The associations between HOXD-AS2 expression and miR-4538 as well as Calmodulin-Dependent Protein Kinase Type II subunit Beta (CAMK2B) levels were conducted through Pearson correlation analysis. A comprehensive analysis identified 141 differentially expressed lncRNAs between 539 LUAD tissues and 59 normal samples. A prognostic marker for overall survival was established by constructing a predictive signature consisting of 9 LRHGs. Subsequently, 474 LUAD samples were categorized into a high or low-risk group based on the median of the risk score. An independent prognostic model was constructed to confirm the validity of this categorization. Further comparisons of the clinicopathological features and LRHG-related pathways were performed between the two groups. Examinations of LRHG expression in two LUAD clusters and of the association between LRHG expression and immune infiltration were also conducted. HOXD-AS2 expression was shown to be elevated in LUAD tissues compared with matched normal tissues, and the serum HOXD-AS2 level was also notably increased in LUAD samples compared with healthy controls. The results of the ROC analysis indicated that the sensitivity and specificity of HOXD-AS2 were higher than that of cytokeratin-19 fragment (CYFRA21-1), which is a serum marker for LUAD. Pearson analyses indicated that miR-4538 level was negatively associated with HOXD-AS2 expression, but CAMK2B level showed positive correlation in LUAD. The results of the present study therefore indicated that the constructed LRHG model, particularly HOXD-AS2, could independently diagnose and predict the prognosis of LUAD, which suggested the underlying mechanism of the HOXD-AS2/miR-4538/CAMK2B, and might offer efficient strategies for LUAD treatment., (© 2024. The Author(s).)

Objective: Recent evidence suggests that elevated levels of PD-L1 expression may be linked to early resistance to TKI and reduced survival in NSCLC with EGFR mutations. This study aimed to characterize the clinical and molecular features of EGFR-mutated lung adenocarcinomas and determine the prognostic significance associated with high PD-L1 expression., Materials and Methods: We conducted a retrospective chart review of 103 consecutive patients with advanced EGFR-mutated NSCLC, who received treatment between 01/01/2016 and 30/12/2020, at our institution., Results: Among the tumors, 17% (n = 18) exhibited high PD-L1 expression (≥50% tumor proportion score), which was associated with a lower prevalence of common EGFR mutations (56% vs. 82%, p = 0.03) and a higher frequency of complex EGFR mutations (28% vs. 7%, p = 0.02). Univariate analysis did not reveal any significant differences in first-line response, progression-free survival, or overall survival between the PD-L1 ≥50% and <50% groups. However, multivariate analysis demonstrated that PD-L1 ≥50% was independently associated with shorter survival (HR = 2.57; 95%CI[1.20-5.55]; p = 0.02), along with male gender (HR = 2.77; 95%CI[1.54-4.19]; p<0.005), presence of liver metastases (HR = 5.80; 95%CI[2.86-11.75]; p<0.005) or brain metastases (HR = 1.99; 95%CI[1.13-3.52]; p = 0.02), and poor general condition at diagnosis (ECOG 3 and 4) (HR = 10.69; 95% CI[4.42-25.85]; p<0.005). Additionally, a trend towards a higher frequency of de novo resistance was observed in the PD-L1 >50% group (7% vs. 17%, p = 0.19)., Conclusion: High PD-L1 expression was more commonly found in lung adenocarcinomas with uncommon and complex EGFR mutations. Furthermore, high PD-L1 expression independently predicted poor survival. These findings warrant validation through prospective studies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Slomka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

With increasing life spans, breast cancer (BC) survivors may face the possibility of developing second primary cancer (SPC), which can considerably shorten survival. Lung cancer (LC) is a common SPC among BC survivors. This study explored the association between these two cancers through Mendelian randomization (MR) analysis. A bidirectional two-sample MR analysis was conducted with BC genome-wide association study (GWAS) data from the Breast Cancer Association Consortium (BCAC) included 228,951 individuals and the GWAS summary statistics from the Transdisciplinary Research in Cancer of the Lung (TRICL) of LC included 112,781 individuals. The IVW method and MR-RAPS method showed a causal effect of overall BC on lung adenocarcinoma (LUAD) (IVW: OR = 1.060, 95% CI = 1.008-1.116, P = 0.024; MR-RAPS: OR = 1.059, 95% CI = 1.005-1.116, P = 0.033), which indicated that patients with BC had an increased risk of LUAD. However, there is no strong evidence for a causal effect of LUAD on BC. Our study revealed a causal effect of BC on second primary LUAD, suggesting that we should intensify screening for second primary LC in BC survivors. Early intervention and treatment for patients with second primary LC are needed to reduce mortality in BC survivors., (© 2024. The Author(s).)

Non-small cell lung adenocarcinoma (LUAD) is the predominant form of lung cancer originating from lung epithelial cells, making it the most prevalent pathological type. Currently, reliable indicators for predicting treatment efficacy and disease prognosis are lacking. Despite extensive validation of autophagy-dependent cell death (ADCD) in solid tumor studies and its correlation with immunotherapy effectiveness and cancer prognosis, systematic research on ADCD-related genes in LUAD is limited. We utilized AddModuleScore, ssGSEA, and WGCNA to identify genes associated with ADCD across single-cell and bulk transcriptome datasets. The TCGA dataset, comprising 598 cases, was randomly divided into training and validation sets to develop an ADCD-related LUAD prediction model. Internal validation was performed using the TCGA validation set. For external validation, datasets GSE13213 (119 LUAD samples), GSE26939 (115 LUAD samples), GSE29016 (39 LUAD samples), and GSE30219 (86 LUAD samples) were employed. We evaluated the model's accuracy and effectiveness in predicting prognostic risk. Additionally, CIBERSORT, ESTIMATE, and ssGSEA techniques were used to explore immunological characteristics, drug response, and gene expression in LUAD. Real-time RT-PCR was conducted to assess variations in mRNA expression levels of the gene XCR1 between cancerous and normal tissues in 10 lung cancer patients. We identified 249 genes associated with autophagy-dependent cell death (ADCD) at both single-cell and bulk transcriptome levels. Univariate COX regression analysis revealed that 18 genes were significantly associated with overall survival (OS). Using LASSO-Cox analysis, we developed an ADCD signature based on five genes (BIRC3, TAP1, SLAMF1, XCR1, and HLA-DMB) and created the ADCD-related risk scoring system (ADCDRS). Validation of this model demonstrated its ability to predict disease prognosis and its correlation with clinical characteristics, immune cell infiltration, and the tumor microenvironment. To enhance clinical applicability, we integrated an ADCDRS nomogram. Furthermore, we identified potential drugs targeting specific risk subgroups. We successfully identified a model based on five ADCD genes to predict disease prognosis and treatment efficacy in LUAD, as well as to assess the tumor immune microenvironment. An efficient and practical ADCDRS nomogram was designed., (© 2024. The Author(s).)

Introduction: Lung cancer is a leading cause of cancer-related deaths, with its incidence continuing to rise. Chromatin remodeling, a crucial process in gene expression regulation, plays a significant role in the development and progression of malignant tumors. However, the role of chromatin regulators (CRs) in lung adenocarcinoma (LUAD) remains underexplored., Methods: This study developed a chromatin regulator-related signature (CRRS) using a 429-combination machine learning approach to predict survival outcomes in LUAD patients. The CRRS model was validated across multiple independent datasets. We also investigated the impact of CRRS on the immune microenvironment, focusing on immune cell infiltration. To identify potential therapeutic targets, TFF1, a chromatin regulator, was knocked down using siRNA in LUAD cells. We assessed its impact through apoptosis analysis, proliferation assays, and in vivo tumor growth studies. Additional validation was performed using Ki67 expression and TUNEL assays., Results: The CRRS accurately predicted survival outcomes and was shown to modulate immune cell infiltration in the tumor microenvironment. High-risk patients demonstrated increased activity in cell cycle regulation and DNA repair pathways, along with distinct mutation profiles and immune responses compared to low-risk patients. TFF1 emerged as a key therapeutic target. Knockdown of TFF1 significantly inhibited LUAD cell proliferation, induced apoptosis, and suppressed in vivo tumor growth. Ki67 and TUNEL assays confirmed the role of TFF1 in regulating tumor growth and cell death., Discussion: These findings highlight the potential of chromatin regulators in prognostic modeling and immune modulation in LUAD. TFF1 was identified as a promising therapeutic target, suggesting that targeting TFF1 could provide new treatment strategies. Further research is warranted to explore its full potential and therapeutic applicability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fan, Chen, Wu, Liang, Shen and Miao.)

Although the initial research focused on glycolysis, mitochondrial oxidative phosphorylation has become a major target of cancer cells. Cytochrome C oxidase assembly factor 6 (COA6) is a conserved assembly factor necessary for complex IV biogenesis. Nevertheless, the clinical predictive value of COA6, especially its correlation with immune cell infiltration in lung adenocarcinoma (LUAD), has not yet been elucidated. COA6 exhibited higher expression levels in LUAD cells and tumor tissues compared to normal tissues. Additionally, heightened COA6 expression was associated with reduced overall survival (OS) and advanced tumor stage. Apart from its role in mitochondrial respiratory processes, COA6 may be involved in the process of antigen binding, immunoglobulin receptor binding. Interestingly, we observed a positive correlation between COA6 expression and tumor mutational burden (TMB), as well as a significant association with decreased immune cell infiltration. COA6 was linked to resistance against gemcitabine and etoposide. We verified that COA6 was highly expressed in LUAD experimentally and cell proliferation was inhibited after COA6 knockdown. Thus, we conclude that the expression of COA6 was correlated with reduced immune cell infiltration. Additionally, COA6 functioned as a biomarker for drug sensitivity and the prognosis of lung adenocarcinoma., (© 2024. The Author(s).)

Background: Surgery is the optimal choice for early invasive mucinous lung adenocarcinoma (IMA). A systematic review and meta-analysis were conducted to explore the prognostic factors for resected IMA., Methods: We systematically reviewed the prognostic role of clinicopathological and genomic factors in resected IMA patients. Eligible studies on the treatment of IMA following the systematic search of PubMed, Embase and the Cochrane Library from January 2015 to January 2024 were identified. Outcomes of interest were overall survival (OS) and disease-free survival/recurrence-free survival (DFS/RFS). The hazard ratio (HR) and 95% confidence interval (CI) were used as impact indicators for systematic review and meta-analysis., Results: Sixteen studies involving 3,484 patients with IMA were included. The results of the combined analysis showed that male and smoking were associated with a worse prognosis. Furthermore, advanced clinical stage, poor differentiation grade, presence of visceral pleural invasion (VPI) and spread through air spaces (STAS), and presence of KRAS mutations were also associated with worse prognosis., Conclusions: Gender, smoking, clinical stage, tumor size, differentiation grading, VPI, STAS and KRAS mutation affect DFS/RFS and OS of IMA patients after surgery. Identifying these factors may aid physicians in developing more individualized treatment plans for resectable IMA patients., (© 2024. The Author(s).)

Background: There is a growing interest in utilizing a combination of brain radiotherapy (RT) and tyrosine kinase inhibitors (TKIs) for patients diagnosed with brain metastases (BM) in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma (LAC). The current status of this treatment strategy remains a subject of debate., Methods: We initiated our study by conducting a comprehensive literature search using the SCI-expanded database of Web of Science Core Collection (WoSCC). We utilized the VOSPviewer software to analyze various aspects of the research, including the year of publication, authorship, keywords, and country.Subsequently, we performed an extensive and systematic literature search on popular online databases. Our primary outcome measures were overall survival (OS) and intracranial progression-free survival (iPFS), both quantified by hazard ratios (HRs). Additionally, for data verification, we included data from patients in non-small cell lung cancer with brain metastasis who underwent therapeutic intervention at the Cancer Prevention and Treatment Center of Sun Yat-sen University and the Radiotherapy Department of Hanzhong Central Hospital between August 2012 and November 2021., Results: The bibliometric analysis revealed an increasing trend in research focused on the combination of RT and TKIs for the management of lung cancer brain metastases over the previous decade. Then, nine studies consistent with the research direction were included for meta-analysis. The meta-analysis showed that the OS (HR = 0.81, 95% confidence interval: 0.69-0.94; P = 0.007) and iPFS (HR = 0.71, 95% confidence interval: 0.61-0.82; P < 0.001) of the combination therapy were significantly prolonged. Finally, 168 EGFR-mutated BM advanced LAC patients in the real world were verified, and the median iPFS of the combination therapy (n = 88 and EGFR-TKIs alone (n = 80) were 16.0 and 9.0 months, respectively, (P < 0.001). The median OS was 29.0 and 27.0 months, respectively, with no dramatic difference (P = 0.188)., Conclusions: Research on EGFR-mutant LAC brain metastasis has turned towards exploring optimal treatment strategies for this condition. Our meta-analysis and real-world data analysis consistently demonstrate that combination therapy offers a substantial improvement in patient survival compared to EGFR-TKI monotherapy. Notably, among patients undergoing salvage radiotherapy (RT), our subgroup analysis reveals that those initially treated with third-generation TKIs experience more significant benefits than those treated with first- or second-generation TKIs., (© 2024. The Author(s).)

Pyroptosis plays an important role in lung adenocarcinoma (LUAD). In this study, we aimed to explore the pyroptosis-related gene (PRG) expression pattern and to identify promising pyroptosis-related biomarkers to improve the prognosis of LUAD. The gene expression profiles and clinical information of LUAD patients were downloaded from the Cancer Genome Atlas (TCGA), and validation cohort information was extracted from the Gene Expression Omnibus database. Gene expression data were analyzed using the limma package and visualized using the ggplot2 package as well as the pheatmap package in R software. Functional enrichment analysis was also performed for the 44 differentially expressed PRGs (DEPRGs). Then, consensus clustering revealed pyroptosis-related tumor subtypes, and differentially expressed genes (DEGs) were screened according to the subtypes. Next, univariate Cox and multivariate Cox regression analyses were used to identify independent prognostic PRGs. After overlapping DEGs and the Lasso regression analysis-based prognostic genes, the predictive risk model was established and validated. Correlation analysis between PRGs and clinicopathological variables was also explored. Finally, the TIMER and TISIDB databases were used to further explore the correlation analysis between immune cell infiltration levels, the risk score, and clinicopathological variables in the predictive risk model. A total of 52 genes from the PubMed were identified as PRGs, and 44 of the 52 genes were pooled as DEPRGs. The most significant GO term was "collagen trimer" (P = 2.46E-13), and KEGG analysis results indicated that 44 DEPRGs were significantly enriched in Salmonella infection (P < 0.001). Then, consensus clustering analysis divided LUAD patients into two clusters, and a total of 79 DEGs were identified according to these cluster subtypes. Subsequently, univariate and multivariate Cox regression analyses were used to identify 12 genes that could serve as independent prognostic indicators and we also performed Lasso regression analysis and screened 23 DEGs. After overlapping 23 DEGs and 12 genes, only 4 (KLRG2, MAPK4, C6 and SFRP5) of 12 genes were selected for the further exploration of the prognostic pattern. Survival analysis results indicated that this risk model effectively predicted the prognosis (P < 0.001). Combined with the correlation analysis results between the 4 genes and clinicopathological variables, C6 and KLRG2 were screened as prognostic genes. In this study, we constructed a predictive risk model and identified two pyroptosis subtype-related gene expression patterns to improve the prognosis of LUAD. Understanding the subtypes of LUAD is helpful for accurately characterizing the LUAD and developing personalized treatment., (© 2024. The Author(s).)

Background: Aberrant fatty acid metabolism (FAM) plays a critical role in the tumorigenesis of human malignancies. However, studies on its impact in lung adenocarcinoma (LUAD) are limited., Methods: We developed a prognostic signature comprising 10 FAM-related genes (GPR115, SOAT2, CDH17, MOGAT2, COL11A1, TCN1, LGR5, SLC34A2, RHOV, and DKK1) using data from LUAD patients in The Cancer Genome Atlas (TCGA). This signature was validated using six independent LUAD datasets from the Gene Expression Omnibus (GEO). Patients were classified into high- and low-risk groups, and overall survival (OS) was compared by Kaplan-Meier analysis. The signature's independence as a prognostic indicator was assessed after adjusting for clinicopathological features. Receiver operating characteristic (ROC) analysis validated the signature. Tumor immune microenvironment (TIME) was analyzed using ESTIMATE and multiple deconvolution algorithms. Functional assays, including CCK8, cell cycle, apoptosis, transwell, and wound healing assays, were performed on MOGAT2-silenced H1299 cells using CRISPR/Cas9 technology., Results: Low-risk group patients exhibited decreased OS. The signature was an independent prognostic indicator and demonstrated strong risk-stratification utility for disease relapse/progression. ROC analysis confirmed the signature's validity across validation sets. TIME analysis revealed higher infiltration of CD8+ T cells, natural killers, and B cells, and lower tumor purity, stemness index, and tumor mutation burden (TMB) in low-risk patients. These patients also showed elevated T cell receptor richness and diversity, along with reduced immune cell senescence. High-risk patients exhibited enrichment in pathways related to resistance to immune checkpoint blockades, such as DNA repair, hypoxia, epithelial-mesenchymal transition, and the G2M checkpoint. LUAD patients receiving anti-PD-1 treatment had lower risk scores among responders compared to non-responders. MOGAT2 was expressed at higher levels in low-risk LUAD patients. Functional assays revealed that MOGAT2 knockdown in H1299 cells promoted proliferation and migration, induced G2 cell cycle arrest, and decreased apoptosis., Conclusions: This FAM-related gene signature provides a valuable tool for prognostic stratification and monitoring of TIME and immunotherapy responses in LUAD. MOGAT2 is identified as a potential anti-tumor regulator, offering new insights into its role in LUAD pathogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fu, Zhang, Fan, Zeng, Feng and Wang.)

Wnt/β-Catenin pathway plays an important role in the occurrence and progression of malignant tumors, especially PD-L1-mediated tumor immune evasion. However, the role of TCF/LEF, an important member of the Wnt/β-catenin pathway, in the tumor immunosuppressive microenvironment of lung adenocarcinoma (LUAD) remains unknown. LUAD tissue-coding RNA expression data from The Cancer Genome Atlas and TIMER databases were used to analyze the expression of TCF/LEF transcription factors and their correlation with various immune cell infiltration. Immunohistochemistry and immunofluorescence were used to detect tissue protein staining in 105 patients with LUAD. LEF1, TCF7, TCF7L1 and TCF7L2 were all aberrantly expressed in the tumor tissues of LUAD patients with the data from The Cancer Genome Atlas (TCGA) database, tumor immune estimation resource (TIMER) database and results of immunohistochemistry, but only LEF1 expression was associated with 5-year overall survival in LUAD patients. LEF1 protein expression was associated with advanced tumor node metastasis (TNM) stage, lymphatic metastasis and local invasion in 105 cases LUAD patients. At the same time, LEF1 mRNA expression was also associated with immunosuppressive microenvironment in LUAD patients with the data from TCGA database and TIMER database. Results of immunohistochemistry and immunofluorescence in tumor tissues of 105 cases LUAD patients showed that there was a positively correlation between LEF1 protein expression and the infiltration of M2 macrophages and Treg cells. LEF1 was highly expressed in tumor tissues of LUAD patients, and highly expressed LEF1 was associated with the immunosuppressive microenvironment of LUAD patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Although advances in immune checkpoint inhibitor (ICI) research have provided a new treatment approach for lung adenocarcinoma (LUAD) patients, their survival is still unsatisfactory, and there are issues in the era of response prediction to immunotherapy., Methods: Using bioinformatics methods, a prognostic signature was constructed, and its predictive ability was validated both in the internal and external datasets (GSE68465). We also explored the tumor-infiltrating immune cells, mutation profiles, and immunophenoscore (IPS) in the low-and high-risk groups., Results: As far as we are aware, this is the first study which introduces a novel prognostic signature model using BIRC5, CBLC, S100P, SHC3, ANOS1, VIPR1, LGR4, PGC, and IGKV4.1. According to multivariate analysis, the 9-immune-related genes (IRGs) signature provided an independent prognostic factor for the overall survival (OS). The low-risk group had better OS, and the tumor mutation burden (TMB) was significantly lower in this group. Moreover, the risk scores were negatively associated with the tumor-infiltrating immune cells, like CD8 + T cells, macrophages, dendritic cells, and NK cells. In addition, the IPS were significantly higher in the low-risk group as they had higher gene expression of immune checkpoints, suggesting that ICIs could be a promising treatment option for low-risk LUAD patients., Conclusion: The combination of these 9-IRGs not only could efficiently predict overall survival of LUAD patients but also show a powerful association with the expression of immune checkpoints and response to ICIs based on IPS; hoping this model paves the way for better stratification and management of patients in clinical practice., (© 2024. The Author(s).)

Angiogenesis, metastasis, and resistance to therapy are all facilitated by cancer-associated fibroblasts (CAFs). A CAF-based risk signature can be used to predict patients' prognoses for Lung adenocarcinoma (LUAD) based on CAF characteristics. The Gene Expression Omnibus (GEO) database was used to gather signal-cell RNA sequencing (scRNA-seq) data for this investigation. The GEO and TCGA databases were used to gather bulk RNA-seq and microarray data for LUAD. The scRNA-seq data were analyzed using the Seurat R program based on the CAF markers. Our goal was to use differential expression analysis to discover differentially expressed genes (DEGs) across normal and tumor samples in the TCGA dataset. Pearson correlation analysis was utilized to discover prognostic genes related with CAF, followed by univariate Cox regression analysis. Using Lasso regression, a risk signature based on CAF-related prognostic genes was created. A nomogram model was created based on the clinical and pathological aspects. 5 CAF clusters were identified in LUAD, 4 of which were associated with prognosis. From 2811 DEGs, 1002 genes were found to be significantly correlated with CAF clusters, which led to the creation of a risk signature with 8 genes. These 8 genes were primarily connected with 41 pathways, such as antigen paocessing and presentation, apoptosis, and cell cycle. Meanwhile, the risk signature was significantly associated with stromal and immune scores, as well as some immune cells. Multivariate analysis revealed that risk signature was an independent prognostic factor for LUAD, and its value in predicting immunotherapeutic outcomes was confirmed. A novel nomogram integrating the stage and CAF-based risk signature was constructed, which exhibited favorable predictability and reliability in the prognosis prediction of LUAD. CAF-based risk signatures can be effective in predicting the prognosis of LUAD, and they may provide new strategies for cancer treatments by interpreting the response of LUAD to immunotherapy., (© 2024. The Author(s).)

Lung adenocarcinoma (LUAD) is a study that examines the prognostic value of lactate metabolism genes in tumor cells, which are associated with clinical prognosis. We analyzed the expression and clinical data for LUAD from The Cancer Genome Atlas database, using the GSE68465 dataset from the Gene Expression Omnibus and the MSigDB database. LASSO Cox regression and stepwise Cox regression were used to identify the optimal lactate metabolism gene signature. Differences in immune infiltration, tumor mutation burden (TMB), and response to immune checkpoint blockade (ICB) therapy were evaluated between groups. LASSO and Cox regression analyses showed an eight-lactate metabolism gene signature for model construction in both TCGA cohort and GSE68465 data, with higher survival outcomes in high-risk groups. The lactate metabolism risk score had an independent prognostic value (hazard ratio: 2.279 [1.652-3.146], P < .001). Immune cell infiltration differed between the risk groups, such as CD8+ T cells, macrophages, dendritic cells, mast cells, and neutrophils. The high-risk group had higher tumor purity, lower immune and stromal scores, and higher TMB. High-risk samples had high tumor immune dysfunction and exclusion (TIDE) scores and low cytolytic activity (CYT) scores, indicating a poor response to ICB therapy. Similarly, most immune checkpoint molecules, immune inhibitors/stimulators, and major histocompatibility complex (MHC) molecules were highly expressed in the high-risk group. The 8-lactate metabolism gene-based prognostic model predicts patient survival, immune infiltration, and ICB response in patients with LUAD, driving the development of therapeutic strategies to target lactate metabolism., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Lactate dehydrogenase is dysregulated in several cancer types. However, the mechanism of its dysregulation in lung cancer is not fully understood. We utilized web-based computational databases to conduct gene expression analysis on LDHA, identified its regulator, and explored their role in the prognosis of lung cancer., Methods: We used various web-based computational tools, including the UALCAN, TIMER2.0, ENCORI, TCGA Portal, OncoDB, and GEPIA2 datasets for lung cancer analysis in this study. We also performed survival, biological processes, and metastasis analysis using various computational tools. We also carried out co-expression functional enrichment analysis using the Enrichr and TIMER databases, multivariate analysis of survival and pathological stage, and transcriptional regulation analysis using the ENCORI and OncoDB datasets. Furthermore, LDHA inhibitor binding of withanolides was analyzed using Auto Dock Tools 1.5.6, LigPlot+, and Pymol., Results: The study found that the higher levels of LDHA gene expression were associated with poor prognosis and overall survival in lung cancer patients. We identified 11 key genes co-expressed with LDHA; out of them, two genes, MKI67 and PGK1, showed a strong positive correlation with LDHA and associated poor survival outcomes in LUAD patients. Furthermore, we also identified hsa-let-7c-5p and TMPO-AS1 as potential regulators of LDHA in LUAD. It might be possible that the TMPO-AS1- hsa-let-7c-5p-LDHA ceRNA network could serve as a potential regulator of aerobic glycolysis in LUAD and can serve as prognostic biomarkers. Further, Withanolides can inhibit the activity of LDHA and can be tested as an adjuvant treatment., Conclusion: We conclude that LDHA is overexpressed in LUAD, and the patients with high expression of LDHA exhibit poor prognosis. Further, the TMPO-AS1-hsa-let-7c-5p-LDHA ceRNA network can regulate aerobic glycolysis, thereby facilitating tumor growth in lung cancer.

Objective: Disulfidptosis was stimulated in high SLC7A11 expression cells starving to glucose. We attempted to identify disulfidptosis-related lncRNAs (DRLs), built a prognostic model to predict survival, and analyzed the tumor microenvironment., Methods: The TCGA database was utilized to procure the pertinent data. By utilizing both Cox regression and the least absolute shrinkage and selection operator (LASSO) method, a risk model based on DRLs was formulated for prognostic evaluation. The ability of survival prediction was validated by multiple approaches. The biological functions were screened through GO, KEGG, and GSEA. Various methods were employed to evaluate the tumor immune environment, which included ESTIMATE, tumor mutation burden (TMB) score, CIBERSORT algorithm, and tumor immune dysfunction and exclusion (TIDE) score., Results: Ninety-one DRLs were recognized, and lncRNA AC092718.4, AL365181.2, AL606489.1, EMSLR, and ENTPD3-AS1 were involved in the risk model. The GEO database was used to verify the influence of these lncRNAs on survival. The following analyses showed that survival could be predicted excellently by the DRLs risk model. The results of enrichment analyses pointed toward the involvement of the cell cycle and IgA production pathways. In the low-risk patient group, there was a notable surge in stromal, immune, and ESTIMATE scores, while the TMB scores took a tumble. Conversely, the high-risk patient group displayed a converse trend. Notably, the group of patients with lower risk scores and higher TMB scores showed the most favorable survival outcomes, underscoring the importance of considering both risk score and TMB in predicting the response to immune checkpoint blockade therapy. Furthermore, patients classified as high-risk might display resistance to both chemotherapy and targeted therapy. Cellular biological experiments proved that lncRNA AC092718.4 promoted invasion, migration, and proliferation abilities in vitro. These results provided valuable insights into the role of DRLs in LUAD and presented a possible effective treatment approach for LUAD., Conclusions: We developed a disulfidptosis-related risk model with 5 lncRNAs that enables survival prediciton for LUAD patients and aids cilinical decisions by forecasting the TME, TMB, and drug sensitivity, making it a valuable tool for outcomes prediction., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The role of solute carrier family 35 member F3 (SLC35F3) in lung adenocarcinoma (LUAD) remains unclear. To address this gap, we conducted a study employing bioinformatics analysis and experimental validation., Methods: This study aimed to examine the expression patterns of SLC35F3 in various cancer types, particularly focusing on LUAD, by analyzing data from the Cancer Genome Atlas (TCGA) database to evaluate its clinical relevance. The research also explored potential regulatory mechanisms of SLC35F3, including its interactions with immune infiltration, tumor mutational burden (TMB), and drug sensitivity in LUAD. The investigation included analyzing SLC35F3 expression in single-cell sequencing of LUAD cells, examining genetic variations of SLC35F3 in LUAD, and assessing SLC35F3 expression in cell lines using quantitative real-time PCR (qRT-PCR)., Results: The aberrant expression of SLC35F3 was observed in both pan-cancer and LUAD. In LUAD patients, a statistically significant increase in SLC35F3 expression was correlated with gender (p < 0.001) and was associated with poorer overall survival (OS) (p = 0.020). The expression of SLC35F3 was identified as an independent prognostic determinant in patients with LUAD (p = 0.032). SLC35F3 exhibited associations with various pathways, including cell cycle and more. SLC35F3 expression demonstrated correlations with immune infiltration, TMB, and some drugs in LUAD. Results indicated significant upregulation of SLC35F3 in both LUAD tissues and cell lines., Conclusions: SLC35F3 may serve as a prognostic biomarker and immunotherapeutic target for patients with LUAD., Clinical Trial Registration: Not applicable., (© 2024 The Author(s). The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Background: Lung cancer, on a global scale, leads to the most common cases of cancer mortalities. Novel therapeutic approaches are urgently needed to disrupt this lethal disease. The rapid development of tumor immunology combining breakthroughs involving fatty acid metabolism brings possibilities. Directing fatty acid metabolism is supposed to help discover potential prognostic biomarkers and treatment targets for lung cancer., Methods: Through searching the GSE140797 dataset, we identified genes related to fatty acid metabolism as well as fatty acid metabolism-related differentially expressed genes (DEGs). We applied various methods to ascertain the independent prognostic value of the DEGs. The methods we utilized entail prognostic analysis, differential expression analysis, as well as univariate and multivariate Cox regression analyses. The lasso Cox regression model was utilized in examining how DEGs correlate with the immune score, immune checkpoint, ferroptosis, methylation, and OCLR score. The expression levels of ACAT1 and ACSL3 in tissues derived from normal lung and lung adenocarcinoma (LUAD) tissues were compared by qRT-PCR., Results: In this study, ACSL3 and ACAT1 were identified as fatty acid metabolism-related genes utilizing independent prognostic value and as a result, the risk prognostic model was built using these factors. qRT-PCR results implied that ACSL3 and ACAT1 expressions were upregulated and downregulated, correspondingly in tumor tissues. Additional evaluations suggested that ACSL3 and ACAT1 were affirmed to be remarkably correlated with the immune score, methylation, immune checkpoint, OCLR score, and ferroptosis., Conclusions: ACSL3 and ACAT1 were effective prognostic biomarkers and potential immunotherapeutic targets in LUAD., (© 2024 The Author(s). The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

The prognosis of poorly differentiated lung adenocarcinoma (PDLA) is determined by many clinicopathological factors. The aim of this study is identifying prognostic factors and developing reliable nomogram to predict the overall survival (OS) and cancer-specific survival (CSS) in patients with PDLA. Patient data from the Surveillance, Epidemiology and End Results (SEER) database was collected and analyzed. The SEER database was used to screen 1059 eligible patients as the study cohort. The whole cohort was randomly divided into a training cohort (n = 530) and a test cohort (n = 529). Cox proportional hazards analysis was used to identify variables and construct a nomogram based on the training cohort. C-index and calibration curves were performed to evaluate the performance of the model in the training cohort and test cohorts. For patients with PDLA, age at diagnosis, gender, tumor size were independent prognostic factors both for overall survival (OS) and cancer-specific survival (CSS), while race and number of nodes were specifically related to OS. The calibration curves presented excellent consistency between the actual and nomogram-predict survival probabilities in the training and test cohorts. The C-index values of the nomogram were 0.700 and 0.730 for OS and CSS, respectively. The novel nomogram provides new insights of the risk of each prognostic factor and can assist doctors in predicting the 1-year, 3-year and 5-year OS and CSS in patients with PDLA., (© 2024. The Author(s).)

The extracellular matrix (ECM) is a complex and dynamic network of cross-linked proteins and a fundamental building block in multicellular organisms. Our study investigates the impact of genes related to the ECM receptor interaction pathway on immune-targeted therapy and lung adenocarcinoma (LUAD) prognosis. This study obtained LUAD chip data (GSE68465, GSE31210, and GSE116959) from NCBI GEO. Moreover, the gene data associated with the ECM receptor interaction pathway was downloaded from the Molecular Signature Database. Differentially expressed genes were identified using GEO2R, followed by analyzing their correlation with immune cell infiltration. Univariate Cox regression analysis screened out ECM-related genes significantly related to the survival prognosis of LUAD patients. Additionally, Lasso regression and multivariate Cox regression analysis helped construct a prognostic model. Patients were stratified by risk score and survival analyses. The prognostic models were evaluated using receiver operating characteristic curves, and risk scores and prognosis associations were analyzed using univariate and multivariate Cox regression analyses. A core gene was selected for gene set enrichment analysis and CIBERSORT analysis to determine its function and tumor-infiltrating immune cell proportion, respectively. The results revealed that the most abundant pathways among differentially expressed genes in LUAD primarily involved the cell cycle, ECM receptor interaction, protein digestion and absorption, p53 signaling pathway, complement and coagulation cascade, and tyrosine metabolism. Two ECM-associated subtypes were identified by consensus clustering. Besides, an ECM-related prognostic model was validated to predict LUAD survival, and it was associated with the tumor immune microenvironment. Additional cross-analysis screened laminin subunit beta 1 (LAMB1) for further research. The survival time of LUAD patients with elevated LAMB1 expression was longer than those with low LAMB1 expression. Gene set enrichment analysis and CIBERSORT analyses revealed that LAMB1 expression correlated with tumor immune microenvironment. In conclusion, a prognostic model of LUAD patients depending on the ECM receptor interaction pathway was constructed. Screening out LAMB1 can become a prognostic risk factor for LUAD patients or a potential target during LUAD treatment., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Lung adenocarcinoma (LUAD), characterized by a low 5-year survival rate, is the most common and aggressive type of lung cancer. Recent studies have shown that tertiary lymphoid structures (TLS), which resemble lymphoid structures, are closely linked to the immune response and tumor prognosis. The functions of the tertiary lymphoid structure-related genes (TLS-RGs) in the tumor microenvironment (TME) are poorly understood. Based on publicly available data, we conducted a comprehensive study of the function of TLS-RGs in LUAD. Initially, we categorized LUAD patients into two TLS and two gene subtypes. Subsequently, risk scores were calculated, and prognostic models were constructed using seven genes (CIITA, FCRL2, GBP1, BIRC3, SCGB1A1, CLDN18, and S100P). To enhance the clinical application of TLS scores, we have developed a precise nomogram. Furthermore, drug sensitivity, tumor mutational burden (TMB), and the cancer stem cell (CSC) index were found to be substantially correlated with the TLS scores. Single-cell sequencing results reflected the distribution of TLS-RGs in cells. Finally, we took the intersection of overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) prognosis-related genes and then further validated the expression of these genes by qRT-PCR. Our in-depth investigation of TLS-RGs in LUAD revealed their possible contributions to the clinicopathological features, prognosis, and characteristics of TME. These findings underscore the potential of TLS-RGs as prognostic biomarkers and therapeutic targets for LUAD, thereby paving the way for personalized treatment strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Pan, Pan, Zeng, Liang and Li.)

Lung cancer remains the leading cause of cancer-related death worldwide, and drug resistance represents the main obstacle responsible for the poor mortality and prognosis. Here, to identify a novel gene signature for predicting survival and drug response, we jointly investigated RNA sequencing data of lung adenocarcinoma patients from TCGA and GEO databases, and identified a ferroptosis-related gene signature. The signature was validated in the validation set and two external cohorts. The high-risk group had a reduced survival than the low-risk group ( P < 0.05). Moreover, the established gene signature was associated with tumor mutation burden, microsatellite instability, and response to immune checkpoint blockade. In addition, four candidate oncogenes ( RRM2 , SLC2A1 , DDIT4 , and VDAC2 ) were identified to be candidate oncogenes using in silico and wet experiments, which could serve as potential therapeutic targets. Collectively, this study developed a novel ferroptosis-related gene signature for predicting prognosis and drug response, and identified four candidate oncogenes for lung adenocarcinoma.

Introduction: The programmed cell death (PCD) plays a key role in the development and progression of lung adenocarcinoma. In addition, immune-related genes also play a crucial role in cancer progression and patient prognosis. However, further studies are needed to investigate the prognostic significance of the interaction between immune-related genes and cell death in LUAD., Methods: In this study, 10 clustering algorithms were applied to perform molecular typing based on cell death-related genes, immune-related genes, methylation data and somatic mutation data. And a powerful computational framework was used to investigate the relationship between immune genes and cell death patterns in LUAD patients. A total of 10 commonly used machine learning algorithms were collected and subsequently combined into 101 unique combinations, and we constructed an immune-associated programmed cell death model (PIGRS) using the machine learning model that exhibited the best performance. Finally, based on a series of in vitro experiments used to explore the role of PSME3 in LUAD., Results: We used 10 clustering algorithms and multi-omics data to categorize TCGA-LUAD patients into three subtypes. patients with the CS3 subtype had the best prognosis, whereas patients with the CS1 and CS2 subtypes had a poorer prognosis. PIGRS, a combination of 15 high-impact genes, showed strong prognostic performance for LUAD patients. PIGRS has a very strong prognostic efficacy compared to our collection. In conclusion, we found that PSME3 has been little studied in lung adenocarcinoma and may be a novel prognostic factor in lung adenocarcinoma., Discussion: Three LUAD subtypes with different molecular features and clinical significance were successfully identified by bioinformatic analysis, and PIGRS was constructed using a powerful machine learning framework. and investigated PSME3, which may affect apoptosis in lung adenocarcinoma cells through the PI3K/AKT/Bcl-2 signaling pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xie, Chen, Tian, Wang, Wang, Zhang, Wang and Lian.)

Background: To explore the abnormal metabolism-related genes that affect the prognosis of patients with lung adenocarcinoma (LUAD), and analyze the relationship with immune infiltration and competing endogenous RNA (ceRNA) network., Methods: Transcriptome data of LUAD were downloaded from the Cancer Genome Atlas database. Abnormal metabolism-related differentially expressed genes in LUAD were screened by the R language. Cox analysis was used to construct LUAD prognostic risk model. Kaplan-Meier test, ROC curve and nomograms were used to evaluate the predictive ability of metabolic related gene prognostic model. CIBERSORT algorithm was used to analyze the relationship between risk score and immune infiltration. The starBase database constructed a regulatory network consistent with the ceRNA hypothesis. IHC experiments were performed to verify the differential expression of ALG3 in LUAD and paracancerous samples., Results: In this study, 42 abnormal metabolism-related differential genes were screened. After survival analysis, the final 5 metabolism-related genes were used as the construction of prognosis model, including ALG3, COL7A1, KL, MST1, and SLC52A1. In the model, the survival rate of LUAD patients in the high-risk subgroup was lower than that in the low-risk group. In addition, the risk score of the constructed LUAD prognostic model can be used as an independent prognostic factor for patients. According to the analysis of CIBERSORT algorithm, the risk score is related to the infiltration of multiple immune cells. The potential ceRNA network of model genes in LUAD was constructed through the starBase database. IHC experiments revealed that ALG3 expression was upregulated in LUAD., Conclusion: The prognostic model of LUAD reveals the relationship between metabolism and prognosis of LUAD, and provides a novel perspective for diagnosis and research of LUAD., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Lung adenocarcinoma (LUAD) significantly contributes to cancer-related mortality worldwide. The heterogeneity of the tumor immune microenvironment in LUAD results in varied prognoses and responses to immunotherapy among patients. Consequently, a clinical stratification algorithm is necessary and inevitable to effectively differentiate molecular features and tumor microenvironments, facilitating personalized treatment approaches., Methods: We constructed a comprehensive single-cell transcriptional atlas using single-cell RNA sequencing data to reveal the cellular diversity of malignant epithelial cells of LUAD and identified a novel signature through a computational framework coupled with 10 machine learning algorithms. Our study further investigates the immunological characteristics and therapeutic responses associated with this prognostic signature and validates the predictive efficacy of the model across multiple independent cohorts., Results: We developed a six-gene prognostic model (MYO1E, FEN1, NMI, ZNF506, ALDOA, and MLLT6) using the TCGA-LUAD dataset, categorizing patients into high- and low-risk groups. This model demonstrates robust performance in predicting survival across various LUAD cohorts. We observed distinct molecular patterns and biological processes in different risk groups. Additionally, analysis of two immunotherapy cohorts (N = 317) showed that patients with a high-risk signature responded more favorably to immunotherapy compared to those in the low-risk group. Experimental validation further confirmed that MYO1E enhances the proliferation and migration of LUAD cells., Conclusion: We have identified malignant cell-associated ligand-receptor subtypes in LUAD cells and developed a robust prognostic signature by thoroughly analyzing genomic, transcriptomic, and immunologic data. This study presents a novel method to assess the prognosis of patients with LUAD and provides insights into developing more effective immunotherapies., (© 2024. The Author(s).)

Lung adenocarcinoma (LUAD) is the dominant histotype of non-small cell lung cancer. Panoptosis, a comprehensive form of programmed cell death, is central to carcinogenesis. In this study, the expression of PANoptosis-related genes (PRGs) and their impact on the development, prognosis, tumor microenvironment, and treatment response of patients with lung adenocarcinoma (LUAD) were systematically evaluated. PRGs were selected from The Cancer Genome Atlas database and Genecards dataset using differential expression analysis. The signature of included PRGs was identified using univariate Cox regression analysis and LASSO regression analysis. Additionally, a nomogram was developed that includes signature and clinical information. Kaplan-Meier survival analysis and receiver operating characteristic curves were used to assess the predictive validity of these risk models. Finally, functional analysis of the selected PRGs in signature and analysis of immune landscape were also performed. Preliminary identification of 10 genes related to PANoptosis has significant implications for prognosis. Subsequently, seven related genes were integrated to classify LUAD patients into different survival risk groups. The prognostic risk score generated from the signature and the TNM stage were as independent prognostic factors and were utilized in creating a nomogram plot. Both the features and the nomogram plot showed accurate performance in predicting the overall survival of LUAD patients. The PRGs were enriched in several biological functions and pathways, and stratified studies were conducted on the differences in immune landscape between high-risk and low-risk groups based on their characteristics. Ultimately, our evaluation focused on the differences in drug treatment efficacy between the high-risk and low-risk groups, providing a foundation for future research directions. Potential associations between PRGs and patient prognosis in LUAD have been identified in this study. Potential biomarkers for clinical application could be considered for the prognostic predictors identified in this study., (© 2024. The Author(s).)

Background: Micropapillary (MPP) adenocarcinoma is considered one of the most aggressive pathological types of lung adenocarcinoma (LADC). This retrospective study aimed to evaluate the prognostic significance and benefit of postoperative adjuvant therapy (PAT) in stage IA LADC patients with different proportions of MPP components., Materials and Methods: We retrospectively examined clinical stage IA LADC patients who underwent surgical resection between August 2012 and December 2019. In terms of the proportion of MPP components (TPM), the tumors were reclassified into three categories: MPP patterns absent (TPMN); low proportions of MPP components (TPML); and high proportions of MPP components (TPMH). The dates of recurrence and metastasis were identified based on physical examinations and were confirmed by histopathological examination., Results: Overall, 505 (TPMN, n = 375; TPML, n = 92; TPMH, n = 38) patients harboring EGFR mutations were enrolled in the study. Male sex (P = 0.044), high pathological stage (P < 0.001), and MPP pathological subtype (P < 0.001) were more frequent in the TPM-positive (TPMP) group than in the TPM-negative (TPMN) group. Five-year disease-free survival (DFS) rates were significantly lower in the TPMP group than in the TPMN group (84.5% vs. 93.4%, P = 0.006). In addition, patients with high proportions (greater than 10%) of MPP components had worse overall survival (OS) (91.0% vs. 98.9%, P = 0.025) than those with low proportions (5%≤ TPM ≤ 10%). However, postoperative EGFR tyrosine kinase inhibitors (TKIs) or adjuvant chemotherapy (ACT) cannot improve DFS and OS between EGFR-mutated patients with different proportions of MPP components., Conclusion: MPP was related to earlier recurrence and shortened survival time, even in stage IA. Further research needs a larger sample size to clarify that EGFR-mutated stage IA patients with MPP components obtain survival benefits from adjuvant therapy., (© 2024. The Author(s).)

The spatial arrangement of immune cells within the tumor microenvironment (TME) and their interactions play critical roles in the initiation and development of cancer. Several advanced technologies such as imaging mass cytometry (IMC) providing the immunological landscape of the TME with single-cell resolution. In this study, we develop a new method to quantify the spatial proximity between different cell types based on single-cell spatial data. Using this method on IMC data from 416 lung adenocarcinoma patients, we show that the proximity between different cell types is more correlated with patient prognosis compared to the traditional features such immune cell density and fractions. Consistent with previous reports, our results validate that proximity of T helper (Th) and B cells to cancer cells is associated with survival benefits. More importantly, we discover that the proximity of M2 macrophages to multiple immune cells is associated with poor prognosis. When Th/B cells are stratified into M2-distal and M2-proximal, the abundance of the former but not the latter category of Th/B cells is correlated with enhanced patient survival. Additionally, the abundance of M2-distal and M2-proximal cytotoxic T cells (Tc) is respectively associated with good and poor prognosis. Our results indicate that the prognostic effect of Th, Tc, and B cells in the tumor microenvironment is modulated by the nearby M2 macrophages. The proposed new method proposed can be readily applied to all single-cell spatial data for revealing functional impact of immune cell interactions., (© 2024. The Author(s).)

Purpose: Invasive mucinous adenocarcinoma (IMA) of the lungs is a rare subtype of lung adenocarcinoma with a limited understanding of its prognosis, particularly in advanced stages. This study aimed to assess the prognosis of patients with advanced IMA by focusing on treatment modalities., Methods: This single-center retrospective study evaluated 33 patients with IMAs diagnosed with advanced-stage disease or disease progression after curative treatment between 2011 and 2021. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). OS and PFS were calculated from the date of the diagnosis of advanced IMA., Results: The study cohort included 13 patients at the initial advanced stage and 20 patients who progressed after curative treatment. Treatment modalities included conventional chemotherapy in 24 patients (72.7%), targeted therapy in seven (21.2%), immunotherapy in 13 (39.4%), and local ablative therapy (LAT) in 13 (39.4%). The median OS was 32 months (95% confidence interval [CI], 2.9-61.0), with LAT significantly associated with improved OS compared to non-LAT treatment (not reached vs. 11.3 months, p = 0.001). However, there was no significant difference in OS based on conventional chemotherapy (p = 0.396), targeted therapy (p = 0.655), or immunotherapy (p = 0.992). In multivariate analysis, LAT remained an independent prognostic factor for OS (hazard ratio, 0.125; 95% CI, 0.026-0.608; p = 0.01). PFS was 8.6 months (95% CI, 3.6-13.7), with no significant differences observed among the treatment modalities., Conclusion: Our findings suggest that LAT may provide favorable survival outcomes in patients with advanced IMA., (© 2024. The Author(s).)

Background: The cancer genome contains several driver mutations. However, in some cases, no known drivers have been identified; these remaining areas of unmet needs, leading to limited progress in cancer therapy. Whole-genome sequencing (WGS) can identify non-coding alterations associated with the disease. Consequently, exploration of non-coding regions using WGS and other omics data such as ChIP-sequencing (ChIP-seq) to discern novel alterations and mechanisms related to tumorigenesis have been attractive these days., Methods: Integrated multi-omics analyses, including WGS, ChIP-seq, DNA methylation, and RNA-sequencing (RNA-seq), were conducted on samples from patients with non-clinically actionable genetic alterations (non-CAGAs) in lung adenocarcinoma (LUAD). Second-level cluster analysis was performed to reinforce the correlations associated with patient survival, as identified by RNA-seq. Subsequent differential gene expression analysis was performed to identify potential druggable targets., Results: Differences in H3K27ac marks in non-CAGAs LUAD were found and confirmed by analyzing RNA-seq data, in which mastermind-like transcriptional coactivator 2 (MAML2) was suppressed. The down-regulated genes whose expression was correlated to MAML2 expression were associated with patient prognosis. WGS analysis revealed somatic mutations associated with the H3K27ac marks in the MAML2 region and high levels of DNA methylation in MAML2 were observed in tumor samples. The second-level cluster analysis enabled patient stratification and subsequent analyses identified potential therapeutic target genes and treatment options., Conclusions: We overcome the persistent challenges of identifying alterations or driver mutations in coding regions related to tumorigenesis through a novel approach combining multi-omics data with clinical information to reveal the molecular mechanisms underlying non-CAGAs LUAD, stratify patients to improve patient prognosis, and identify potential therapeutic targets. This approach may be applicable to studies of other cancers with unmet needs., (© 2024. The Author(s).)

Introduction: The connection between aging and cancer is complex. Previous research has highlighted the association between the aging process of lung adenocarcinoma (LUAD) cells and the immune response, yet there remains a gap in confirming this through single-cell data validation. Here, we aim to develop a novel aging-related prognostic model for LUAD, and verify the alterations in the genome and immune microenvironment linked to cellular senescence., Methods: We integrated a comprehensive collection of senescence genes from the GenAge and CellAge databases and employed the least absolute shrinkage and selection operator (LASSO) Cox analysis to construct and validate a novel prognostic model for LUAD. This model was then utilized to examine the relationship between aging, tumor somatic mutations, and immune cell infiltration. Additionally, we explored the heterogeneity of senescence and intercellular communication within the LUAD tumor microenvironment (TME) through single-cell transcriptomic data analysis., Results: By exploring the expression profiles of 586 cellular senescence-related genes in 428 LUAD patients, we constructed an aging-related genes (ARGs) risk model included 10 ARGs and validated it as an independent prognostic predictor for LUAD patients. Notably, patients with low aging scores (LAS group) exhibited better survival, lower tumor mutation burden (TMB), lower somatic mutation frequency, lower tumor proliferation rate, and an immune activated phenotype compared to patients with high aging scores (HAS group). While the HAS group was enriched in tumor cells and showed a lower infiltration of CD8-CCR7, CD8- CXCL13, CD8-GNLY, FCGR3A NK cells, XCL1 NK cells, plasma cell (PC) and other immune subsets. Furthermore, the SPP1 and TENASCIN pathways, associated with tumor immune escape and tumor progression, were also enriched in the HAS group. Additionally, our study also indicated that senescence levels were heterogeneous in the LUAD tumor microenvironment (TME), especially with tumor cells in the LAS group showing higher age scores compared to those in the HAS group., Conclusions: Collectively, our findings underscore that ARRS through ARGs serves as a robust biomarker for the prognosis in LUAD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ru, Cui, Wu, Tan, An, Wu, Ma, Hao, Xiao, Bai, Liu, Xia and Zhao.)

The ribosomal protein L22-like1 (RPL22L1) is a constituent of the 60 S ribosomal subunit whose function in lung adenocarcinoma (LUAD) remains ambiguous. This study aims to elucidate the role of RPL22L1 in LUAD through a thorough analysis and experimental validation. Our findings indicate that RPL22L1 exhibits abnormal expression patterns in various cancer types, including LUAD. Moreover, a statistically significant association was observed between elevated levels of RPL22L1 expression in LUAD patients and several clinical parameters, such as pathological stage (p = 0.0083) and gender (p = 0.0038). The high expression of RPL22L1 in LUAD demonstrated a significant association with poorer overall survival (OS) (p = 0.005), progression-free survival (PFS) (p = 0.027), and disease-specific survival (p = 0.015). The expression of RPL22L1 in LUAD (p = 0.005) was identified as an independent prognostic factor. Additionally, RPL22L1 expression in LUAD was found to be correlated with immune infiltration, immune checkpoint genes, TMB/MSI, and mRNAsi. Notably, the expression of RPL22L1 exhibited significant negative correlations with 1-BET-762, Trametinib, and WZ3105 in LUAD. The RPL22L1 gene exhibited up-regulation in multiple individual cells of LUAD, leading to a comparatively shorter PFS in the RPL22L1 variant group as opposed to the RPL22L1 variant-free group in LUAD. Significantly increased expression of RPL22L1 was noted in LUAD cell lines, where it was found to enhance the growth and metastasis of LUAD cells by suppressing the MDM2/P53 signaling pathway. Therefore, RPL22L1 may serve as a promising prognostic biomarker and therapeutic target for patients with LUAD.

Objectives: The pro-oncogenic effects of NCAPD2 have been extensively studied across various tumor types; however, its precise role within the context of lung adenocarcinoma (LUAD) remains elusive. This study aims to elucidate the biological functions of NCAPD2 in LUAD and unravel the underlying mechanistic pathways., Methods: Utilizing bioinformatics methodologies, we explored the differential expression of NCAPD2 between normal and tumor samples, along with its correlations with clinical-pathological characteristics, survival prognosis, and immune infiltration., Results: In the TCGA-LUAD dataset, tumor samples demonstrated significantly elevated levels of NCAPD2 expression compared to normal samples ( p < 0.001). Clinically, higher NCAPD2 expression was notably associated with advanced T, N, and M stages, pathologic stage, gender, smoking status, and diminished overall survival (OS). Moreover, differentially expressed genes (DEGs) associated with NCAPD2 were predominantly enriched in pathways related to cell division. Immune infiltration analysis revealed that NCAPD2 expression levels were linked to the infiltration of memory B cells, naïve CD4+ T cells, activated memory CD4+ T cells, and M1 macrophages. In vitro experiments demonstrated that silencing NCAPD2 suppressed LUAD cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and cell cycle progression., Conclusions: In summary, NCAPD2 may represent a promising prognostic biomarker and novel therapeutic target for LUAD., Competing Interests: The authors declare that there is no possible conflict of interest., (© 2024 The Authors.)

Background: Lymphocyte antigen 9 (LY9) participates in the development of several tumors and diseases but has not been reported yet in lung adenocarcinoma (LUAD)., Methods: First, we analyzed the expression and prognostic value of LY9 in pan-cancer, including LUAD. Additionally, we conducted a correlation analysis of LY9 expression in LUAD with immune cell infiltration using the TIMER database and the CIBERSORT algorithm, and with immune checkpoints using the GEPIA database. Also, we constructed a potential ceRNA network for LY9. Furthermore, we explored LY9-related pathways by Gene Set Enrichment Analysis (GSEA). Finally, validation of differential expression at the mRNA level was obtained from the GEO database. We collected LUAD tissues for Quantitative Real-time PCR (qRT-PCR) to verify the expression of LY9, CD8, and CD4 and calculated the correlation between them. We also conducted immunohistochemistry (IHC) to verify the protein expression of LY9., Results: Results showed that LY9 was highly expressed in various tumors, including LUAD. Besides, patients with high LY9 expression presented longer overall survival (OS) and more multiple lymphocyte infiltrations. The expression of LY9 in LUAD strongly and positively correlates with multiple immune cell infiltration and immune checkpoints. The functional enrichment analysis indicated that LY9 was involved in multiple immune-related pathways and non-small cell lung cancer. Moreover, a ceRNA regulatory network of LINC00943-hsa-miR-141-3p-LY9 might be involved. Finally, GSE68465 dataset confirmed differential expression of LY9 mRNA levels in LUAD and the qRT-PCR results verified LY9 had a strong and positive correlation with CD4 and CD8 T cells. Unfortunately, IHC did not detect the expression of LY9 protein level in tumor tissues and WB experiments validated the protein expression of LY9 in the OCI-AML-2 cell line., Conclusions: Therefore, we hypothesized that LY9 could serve as a potential, novel prognostic biomarker for LUAD and could predict immunotherapy efficacy at the mRNA level., Competing Interests: The authors declare there are no competing interests., (©2024 Deng et al.)

G0 arrest (G0A) is widely recognized as a crucial factor contributing to tumor relapse. The role of genes related to G0A in lung adenocarcinoma (LUAD) was unclear. This study aimed to develop a gene signature based on for LUAD patients and investigate its relationship with prognosis, tumor immune microenvironment, and therapeutic response in LUAD. We use the TCGA-LUAD database as the discovery cohort, focusing specifically on genes associated with the G0A pathway. We used various statistical methods, including Cox and lasso regression, to develop the model. We validated the model using bulk transcriptome and single-cell transcriptome datasets (GSE50081, GSE72094, GSE127465, GSE131907 and EMTAB6149). We used GSEA enrichment and the CIBERSORT algorithm to gain insight into the annotation of the signaling pathway and the characterization of the tumor microenvironment. We evaluated the response to immunotherapy, chemotherapy, and targeted therapy in these patients. The expression of six genes was validated in cell lines by quantitative real-time PCR (qRT-PCR). Our study successfully established a six-gene signature (CHCHD4, DUT, LARP1, PTTG1IP, RBM14, and WBP11) that demonstrated significant predictive power for overall survival in patients with LUAD. It demonstrated independent prognostic value in LUAD. To enhance clinical applicability, we developed a nomogram based on this gene signature, which showed high reliability in predicting patient outcomes. Furthermore, we observed a significant association between G0A-related risk and tumor microenvironment as well as drug susceptibility, highlighting the potential of the gene signature to guide personalized treatment strategies. The expression of six genes were significantly upregulated in the LUAD cell lines. This signature holds the potential to contribute to improved prognostic prediction and new personalized therapies specifically for LUAD patients., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

To compare the pathological results and long-term survival results of early surgery and surgery after at least one year follow-up for ground-glass component predominant lung adenocarcinoma patients. From January 1, 2013 to August 31, 2017, a total of 279 patients with ground-glass nodules (GGNs) undergoing surgical resection and pathologically proved to be pulmonary adenocarcinoma were included in this study. All patients were divided into early surgery group (ES Group) (210 cases) and surgery after follow-up group (FS Group) (69 cases). Patients in FS group experienced at least one year surveillance. Clinical and imaging features were analyzed by using univariate analysis. After analysis, there was no statistical difference in pathological results and long-term prognosis between the two groups. In the follow-up group, grown GGNs have proved to have more aggressive pathological results. The one-year follow-up may be a feasible management method for patients with ground-glass component predominant GGN., (© 2024. The Author(s).)

Background: Hepatoid adenocarcinoma of the lung (HAL) is a distinctly uncommon subtype of lung adenocarcinoma (LAC), characterized by hepatoid features and an alarmingly low 5-year survival rate of approximately 8%. The scarcity of information on this condition has contributed to the absence of standardized treatment protocols, and the molecular underpinnings of its pathogenesis remain largely unexplored. To bridge these gaps, this study compiled data from 191 primary HAL patients to delineate treatment patterns, prognostic factors, and potential pathogenic mechanisms., Methods: This study was divided into two cohorts: cohort 1, comprising 110 patients extracted from the Surveillance, Epidemiology, and End Results (SEER) database, and cohort 2, consisting of 70 patients identified through a comprehensive literature review via the PubMed, Web of Science, and Scopus databases, in addition to 11 patients from Tongji Hospital. The Cox proportional hazards regression model was employed to identify independent prognostic factors. Kaplan-Meier survival curves were generated to assess the impact of treatment modalities centered around surgery and chemotherapy. Moreover, this study evaluated the efficacy of first-line treatment regimens and conducted Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses on identified mutated genes., Results: The demographic and clinical profile of HAL patients typically comprises older individuals who are smokers, with a predisposition for diagnosis at advanced disease stages, culminating in a high mortality rate. Key prognostic indicators identified included disease stage, chemotherapy and surgical interventions. The study suggests a treatment strategy that advocates chemotherapy for patients with stage IV HAL and surgery for those with non-stage IV disease. The combination of paclitaxel and platinum-based chemotherapy emerged as an efficacious first-line treatment, with the integration of immunotherapy and targeted therapies showing potential benefits. Genetic analysis underscored similarities between HAL and LAC, particularly highlighting aberrant kinase activity (serine, threonine, and tyrosine) and the activation of PI3K-Akt and MAPK signaling pathways as contributing factors to HAL pathogenesis., Conclusion: Despite its relatively rare occurrence, this study underscores the significance of treatment strategies and concludes probable prognostic factors. Due to limited reports, a deeper understanding of the molecular mechanisms driving tumorigenesis and progression in HAL is needed., (© 2024. The Author(s).)

Background: The collaboration between methylation and the lung adenocarcinoma (LUAD) occurrence and development is closes. Long noncoding RNA (lncRNA), as a regulatory factor of various biological functions, can be used for cancer diagnosis. Our study aimed to construct a robust methylation-related lncRNA signature of LUAD., Methods: In the Cancer Genome Atlas (TCGA) dataset, we download the RNA expression data and clinical information of LUAD cases. To develop the best prognostic signature based on methylation-related lncRNAs, Cox regression analyses were utilized. Using Kaplan-Meier analysis, overall survival rates were compared between risk category included both low- and high-risk patients. To categorize genes according to their functional significance, GSEA (Subramanian et al, 2005) was used. Single-sample gene set enrichment analysis (ssGSEA) was used to further reveal the potential molecular mechanism of the methylation-related lncRNA prognostic model in immune infiltration. Using TRLnc (http://www.licpathway.net/TRlnc) and lncRNASNP to analyse the SNP sites and TRLnc of these 18 lncRNAs. LncSEA website was used to analyse 18 lncRNA in the process of tumour development and development. Go was used to analyse the enriched pathways enriched by TFs (transcription factors), Cerna networks, and proteins bound to each other of these 18 lncRNAs. The 'prophetic' package was used to analyse the value of this prognostic model in guiding personalized immunotherapy., Results: In this study, we identified 18 methylation-related lncRNAs (AP002761.1, AL118558.3, CH17-340M24.3, AL353150.1, AC004687.1, LINC00996, AF186192.1, HSPC324, AC087752.3, FAM30A, AC106047.1, AC026355.1, ABALON, LINC01843, AL606489.1, NKILA, AP001453.2, GSEC) to establish a methylation-related lncRNA signature that can detect patients prognosis in LUAD. The enriched pathways enriched by proteins interacting with 18 lncRNAs are mainly EMT, hypoxia, stemness and proliferation, among which LINC00996 and AF186192.1 are regulated by multiple tumour associated transcription factors, such as TP53 and TP63, and fam30a and mRNA form a Cerna network. There are 2319 SNP loci in LINC00996, 36 of which are risk SNP loci and 205 SNP loci in af186192.1; AF186192.1 affects 95 conserved miRNAs and 123 non-conserved miRNAs, promotes the binding of 149 pairs of miRNAs: lncRNAs and inhibits the binding of 95 pairs of miRNAs: lncRNAs. The ROC curve demonstrated that the established methylation-related lncRNA signature was more effective in predicting the prognosis of patients in LUAD than the clinicopathological parameters. Our research has confirmed that patients in the high-risk group which was separated by the risk score model based on methylation-related lncRNA had shorter OS. According to GSEA, the high-risk group had a predominantly tumour- and immune-related pathway enrichment. A significant association was shown by ssGSEA between predictive signature and immune status in LUAD patients. In addition, principal component analysis (PCA) demonstrated the prognostic and predictive value of our signature. The correlation between the predictive signature of methylation-related lncRNA and IC50 of conventional chemotherapy drugs can provide personalized chemotherapy regimens for LUAD patients. Methylation-related lncRNA signature can effectively predict DFS of patients in LUAD., (© 2024 The Author(s). The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Background: Lung adenocarcinoma is a high-mortality rate cancer. Within this category, Lung mucinous adenocarcinoma (LMAC) is a rare and distinct subtype of lung adenocarcinoma necessitating further investigation. The study was launched to compare the difference of survival features between LMAC and lung non-mucinous adenocarcinoma (LNMAC) and to investigate the significance and demand for developing a new staging system tailored to LMAC., Methods: This retrospective study assessed the suitableness of the current staging system for LMAC. It compared the overall survival (OS) between LMAC and LNMAC from 2004 to 2020 (LNMAC: 160,387; LMAC: 6,341) and instituted a novel classification framework for LMAC based on US population. Verification group consisting of patients from two Chinese medical centers from 2010 to 2018 (n = 392) was set to ascertain the applicability of this novel system. The primary endpoint was OS. To minimize the bias, propensity score match (PSM) was employed. Survival analysis and Log-rank test were executed to explore the survival features of LMAC., Results: The results indicated that the existed staging system was not suitable for LMAC. Patients diagnosed with LMAC exhibited a superior OS compared to those with LNMAC in stage IA2 (P < 0.0001), IA3 (P < 0.0001), IB (P = 0.0062), IIA (P = 0.0090), IIB (P = 0.0005). In contrast, a worse OS in stage IVA (P = 0.0103) was found in LMAC patients. The novel classification system proposed for LMAC proved to be highly applicable and demonstrated substantial efficacy, as confirmed by the verification group., Conclusion: The newly established classification system was more effective for LMAC, but it necessitates large-scale verification to confirm its applicability and reliability., (© 2024. The Author(s).)

Introduction: Tryptophan metabolism is strongly associated with immunosuppression and may influence lung adenocarcinoma prognosis as well as tumor microenvironment alterations., Methods: Sequencing datasets were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. Two different clusters were identified by consensus clustering, and prognostic models were established based on differentially expressed genes (DEGs) in the two clusters. We investigated differences in mutational landscapes, enrichment pathways, immune cell infiltration, and immunotherapy between high- and low-risk scoring groups. Single-cell sequencing data from Bischoff et al. were used to identify and quantify tryptophan metabolism, and model genes were comprehensively analyzed. Finally, PTTG1 was analyzed at the pan-cancer level by the pan-TCGA cohort., Results: Risk score was defined as an independent prognostic factor for lung adenocarcinoma and was effective in predicting immunotherapy response in patients with lung adenocarcinoma. PTTG1 is one of the key genes, and knockdown of PTTG1 in vitro decreases lung adenocarcinoma cell proliferation and migration and promotes apoptosis and down-regulation of tryptophan metabolism regulators in lung adenocarcinoma cells., Discussion: Our study revealed the pattern and molecular features of tryptophan metabolism in lung adenocarcinoma patients, established a model of tryptophan metabolism-associated lung adenocarcinoma prognosis, and explored the roles of PTTG1 in lung adenocarcinoma progression, EMT process, and tryptophan metabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Zhang, Zuo, Chen, Wang, Xie, Ma, Min, Wang and Lian.)

Background: This study aimed to identify the associations between individual KRAS, STK11, KEAP1, or TP53 mutations, as well as the comutation status of these genes, and the tumor mutation burden (TMB) with clinical outcomes of lung adenocarcinoma patients treated with immune checkpoint inhibitors (ICIs)., Methods: We collected data from patients with lung adenocarcinoma treated with ICIs from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database between June 2019 and August 2023. The main endpoints were the treatment response and overall survival (OS)., Results: Among 343 patients with lung adenocarcinoma, 61 (18%), 69 (20%), 41 (12%), and 222 (65%) patients had KRAS, STK11, KEAP1, and TP53 mutations, respectively. An overall objective response was observed in 94 of 338 patients (28%), including 2 (1%) who achieved a complete response and 92 (27%) who achieved a partial response. Patients with STK11, KEAP1, or TP53 mutations had a significantly greater TMB (P<0.001). According to the univariate analysis, the treatment response was significantly correlated with TP53 mutation in both the general (P = 0.041) and KRAS wild-type (P = 0.009) populations. KEAP1 and TP53 mutations were associated with worse OS among assessable patients (hazard ratio (HR) = 2.027, P = 0.002; HR = 1.673, P = 0.007, respectively) and among patients without KRAS mutations (HR = 1.897, P = 0.012; HR = 1.908, P = 0.004, respectively). According to the multivariate analysis, KEAP1 (HR = 1.890, P = 0.008) and TP53 (HR = 1.735, P = 0.011) mutations were found to be independent factors for OS., Conclusions: STK11, KEAP1, and TP53 mutations are significantly associated with a high TMB. TP53 mutation could affect the treatment response to some degree, and both KEAP1 and TP53 mutations resulted in inferior OS in the general patient population and in those with KRAS-wild-type lung adenocarcinoma, indicating that KEAP1 and TP53 mutations might act as prognostic factors for ICI treatment in lung adenocarcinoma patients., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Yuichi Ando reports research funds and personal fees from Chugai Pharmaceutical Co., Ltd., research funds from BeiGene. Ltd and Geo Holdings Corporation, and personal fees from Bayer Holding Ltd. The other authors have no conflicts of interest to declare., (Copyright: © 2024 Liang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Lung adenocarcinoma accounts for the majority of lung cancer cases and impact survival rate of patients severely. Immunotherapy is an effective treatment for lung adenocarcinoma but is restricted by many factors including immune checkpoint expression and the inhibitory immune microenvironment. This study aimed to explore the immune microenvironment in lung adenocarcinoma via disulfidptosis., Methods: Public datasets of lung adenocarcinoma from the TCGA and GEO was adopted as the training and validation cohort. Based on the differences in the expression of disulfidptosis -related genes, a glucose metabolism and immune response prognostic model was constructed. The prognostic value and clinical relationship of the model were further explored. Immune-related analyses were performed according to CIBERSORT, ssGSEA, TIDE, IPS., Results: We verified that the model could accurately predict the survival expectancy of lung adenocarcinoma patients. Patients with lung adenocarcinoma and a low-risk score had better survival outcomes according to the model. Moreover, the high-risk group tended to have an immunosuppressive effect, as reflected by the immune cell components, phenotypes and functions. We also found that the clinically relevant immune checkpoint CTLA-4 was significantly higher in low-risk group (P<0.05), indicating that the high-risk group may suffer worse tumor immunotherapy efficacy. Finally, we found that this model has accurate predictive value for the efficacy of immune checkpoint blockade in non-small cell lung cancer (P<0.05)., Conclusion: The prognostic model demonstrated the feasibility of predicting survival and immunotherapy efficacy via disulfidptosis-related genes and will facilitate the development of personalized anticancer therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Li, Wang, Liu, Chen, Li, Li, Song and Li.)

Purpose: Extracellular heat shock protein 90 AA1(eHSP90α) is intricately linked to tumor progression and prognosis. This study aimed to investigate the difference in the value of eHSP90α in post-treatment response assessment and prognosis prediction between exon 19 deletion(19DEL) and exon 21 Leu858Arg(L858R) mutation types in lung adenocarcinoma(LUAD)., Methods: We analyzed the relationship between the expression of eHSP90α and clinicopathological features in 89 patients with L858R mutation and 196 patients with 19DEL mutation in LUAD. The Kaplan-Meier survival curve was used to determine their respective cut-off values and analyze the relationship between eHSP90α expression and the survival time of the two mutation types. The area under the curve (AUC) was used to evaluate the diagnostic performance of biomarkers. Then, the prognostic model was developed using the univariate-Cox multivariate-Cox and LASSO-multivariate logistic methods., Results: In LUAD patients, eHSP90α was positively correlated with carcinoembryonic antigen(CEA), carbohydrate antigen 125(CA125), and carbohydrate antigen 153(CA153). The truncated values of eHSP90α in L858R and 19DEL patients were 44.5 ng/mL and 40.8 ng/mL, respectively. Among L858R patients, eHSP90α had the best diagnostic performance (AUC = 0.765), and higher eHSP90α and T helper cells(Th cells) expression were significantly related to shorter overall survival(OS) and worse treatment response. Also, high eHSP90a expression and short progression-free survival(PFS) were significantly correlated. Among 19DEL patients, CEA had the best diagnostic efficacy (AUC = 0.734), and CEA and Th cells were independent prognostic factors that predicted shorter OS. Furthermore, high CA125 was significantly associated with short PFS and poor curative effect., Conclusions: eHSP90α has a better prognostic value in LUAD L858R patients than 19DEL, which provides a new idea for clinical diagnosis and treatment., (© 2024. The Author(s).)

After the recommendation of computed tomography as a routine procedure for lung cancer screening, an increasing number of young adults have been diagnosed with pulmonary ground-glass opacity (GGO). Up to 63% of pulmonary nodules with a GGO component can be malignant. Since young cancer patients have limited exposure to environmental mutagens, they have special characteristics and needs. This study sought to compare the clinicopathological characteristics of young and old patients with GGO-associated lung adenocarcinoma (GGO-LUAD). Clinicopathological data from 203 patients who underwent video-assisted thoracoscopic surgery between January 2018 and April 2020 for pulmonary GGO component nodules were reviewed. Lung nonmucinous adenocarcinoma patients younger than 40 years old and older than 40 years old were enrolled: 103 patients ≤ 40 years old and 100 patients > 40 years old. The relevant clinicopathological features, including sex, smoking status, tumor size, pathological characteristics, radiographic features and prognosis of pulmonary nodules, were evaluated. Univariate analyses were applied for comparisons between groups. The differences in baseline characteristics (sex, smoking status, tumor location) between the different age groups were not significant. Young patients were more likely to have tumors < 1 cm in size, while older patients predominantly had tumors > 2 cm in size. The mean percentage of invasive adenocarcinoma was greater in the elderly group. Young and older patients seemed to have similar subtypes of adenocarcinoma (p > 0.05) but had different degrees of differentiation (p < 0.001). The 3-year overall survival (OS) and recurrence-free survival (RFS) of the young group were 100% and 99.03%, respectively, while the 3-years OS and RFS of the older group were 99% and 98%, respectively. Our work revealed that young patients with malignant pulmonary nodules and GGOs have distinct pathological subtypes. Patients with GGOs of different ages have different clinicopathological characteristics. The 3-year prognosis of young patients with malignant pulmonary nodules with GGOs is satisfactory., (© 2024. The Author(s).)

Gamma knife radiosurgery (GKRS) is recommended as the first-line treatment for brain metastases of lung adenocarcinoma (LUAD) in many guidelines, but its specific mechanism is unclear. We aimed to study the changes in the proteome of brain metastases of LUAD in response to the hyperacute phase of GKRS and further explore the mechanism of differentially expressed proteins (DEPs). Cancer tissues were collected from a clinical trial for neoadjuvant stereotactic radiosurgery before surgical resection of large brain metastases (ChiCTR2000038995). Five brain metastasis tissues of LUAD were collected within 24 h after GKRS. Five brain metastasis tissues without radiotherapy were collected as control samples. Proteomics analysis showed that 163 proteins were upregulated and 25 proteins were downregulated. GO and KEGG enrichment analyses showed that the DEPs were closely related to ribosomes. Fifty-three of 70 ribosomal proteins were significantly overexpressed, while none of them were underexpressed. The risk score constructed from 7 upregulated ribosomal proteins (RPL4, RPS19, RPS16, RPLP0, RPS2, RPS26 and RPS25) was an independent risk factor for the survival time of LUAD patients. Overexpression of ribosomal proteins may represent a desperate response to lethal radiotherapy. We propose that targeted inhibition of these ribosomal proteins may enhance the efficacy of GKRS., (© 2024. The Author(s).)

To investigate the role of TopBP1-interacting checkpoint and replication regulator (TICRR) in the tumorigenesis and prognosis of lung adenocarcinoma (LUAD) patients. Wilcoxon signed-rank test and logistic regression were utilized to analyze the relationship between clinical characteristics and TICRR expression in LUAD from TCGA dataset. Kaplan-Meier plots and Cox regressions were used to assess the impact of TICRR impact on prognosis. ROC curves and nomograms were generated to further evaluate the relationship between TICRR expression and the risk of LUAD. Gene set enrichment analysis (GSEA) was conducted on TCGA dataset, and ssGSEA was employed to investigate the association between TICRR and immune infiltrates. The results showed that high TICRR expression was significantly associated with various clinical factors including gender, age, pathological stage, T stage, N stage, M stage, outcome of primary therapy and smoking status. ROC curves also demonstrated that TICRR was a promising biomarker for molecular pathology diagnosis in LUAD patients (AUC = 0.952). Further analysis using gene ontology (GO) term enrichment and GSEA revealed an abnormal correlation between TICRR expression and cell division. Interestingly, ssGSEA analysis showed that TICRR expression correlated with multiple immune cell types, such as Th2 cell, TFH cell, mast cell, iDC, eosinophils, and dendritic cell. Lastly, the KM-plotters indicated that LUAD patients with high TICRR expression obtained worse life expectancy (P < .001). TICRR has proven to be a valuable tool in predicting disease progression and prognosis in patients with LUAD, thereby establishing itself as a fitting biomarker for forecasting overall survival (OS) of LUAD patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The aim of this study was to investigate the correlation between m 6 A methylation regulators and cell infiltration characteristics in tumor immune microenvironment (TIME), so as to help understand the immune mechanism of early-stage lung adenocarcinoma (LUAD)., Methods: The expression and consensus cluster analyses of m 6 A methylation regulators in early-stage LUAD were performed. The clinicopathological features, immune cell infiltration, survival and functional enrichment in different subtypes were analyzed. We also constructed a prognostic model. Clinical tissue samples were used to validate the expression of model genes through real-time polymerase chain reaction (RT-PCR). In addition, cell scratch assay and Transwell assay were also performed., Results: Expression of m 6 A methylation regulators was abnormal in early-stage LUAD. According to the consensus clustering of m 6 A methylation regulators, patients with early-stage LUAD were divided into two subtypes. Two subtypes showed different infiltration levels of immune cell and survival time. A prognostic model consisting of HNRNPC, IGF2BP1 and IGF2BP3 could be used to predict the survival of early-stage LUAD. RT-PCR results showed that HNRNPC, IGF2BP1 and IGF2BP3 were significantly up-regulated in early-stage LUAD tissues. The results of cell scratch assay and Transwell assay showed that overexpression of HNRNPC promotes the migration and invasion of NCI-H1299 cells, while knockdown HNRNPC inhibits the migration and invasion of NCI-H1299 cells., Conclusions: This work reveals that m 6 A methylation regulators may be potential biomarkers for prognosis in patients with early-stage LUAD. Our prognostic model may be of great value in predicting the prognosis of early-stage LUAD.