Real-world efficacy of adjuvant therapy for totally resected stage I lung adenocarcinoma patients with pathological high-risk factors: propensity score analysis.

BACKGROUND: We investigated the real-world efficacy of adjuvant therapy for stage I lung adenocarcinoma patients with pathological high-risk factors. METHODS: Study participants were enrolled from November 1, 2016 and December 31, 2020. Clinical bias was balanced by propensity score matching. Disease-free survival (DFS) outcomes were compared by Kaplan-Meier analysis. The Cox proportional hazards regression was used to identify survival-associated factors. p ≤ 0.05 was the threshold for statistical significance. RESULTS: A total of 454 patients, among whom 134 (29.5%) underwent adjuvant therapy, were enrolled in this study. One hundred and eighteen of the patients who underwent adjuvant therapy were well matched with non-treatment patients. Prognostic outcomes of the treatment group were significantly better than those of the non-treatment group, as revealed by Kaplan-Meier analysis after PSM. Differences in prevention of recurrence or metastasis between the targeted therapy and chemotherapy groups were insignificant. Adjuvant therapy was found to be positive prognostic factors, tumor size and solid growth patterns were negative. CONCLUSIONS: Adjuvant therapy significantly improved the DFS for stage I lung adenocarcinoma patients with high-risk factors. Larger prospective clinical trials should be performed to verify our findings.

The expression characteristic and prognostic role of Siglec-15 in lung adenocarcinoma.

Sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) has been identified as an immune suppressor and a promising candidate for immunotherapy of cancer management. However, the association between Siglec-15 expression and clinicopathological features of lung adenocarcinoma (LUAD), especially the prognostic role, is not fully elucidated. In this present study, a serial of bioinformatics analyses in both tissue and cell levels were conducted to provide an overview of Siglec-15 expression. Real-time quantitative PCR (qPCR) test, western blotting assay, and immunohistochemistry (IHC) analyses were conducted to evaluate the expression of Siglec-15 in LUAD. Survival analysis and Kaplan-Meier curve were employed to describe the prognostic parameters of LUAD. The results of bioinformatics analyses demonstrated the up-regulation of Siglec-15 expression in LUAD. The data of qPCR, western blotting, and IHC analyses further proved that the expression of Siglec-15 in LUAD tissues was significantly increased than that in noncancerous tissues. Moreover, the expression level of Siglec-15 protein in LUAD was substantially associated with TNM stage. LUAD cases with up-regulated Siglec-15 expression, positive N status, and advance TNM stage suffered a critical unfavorable prognosis. In conclusion, Siglec-15 could be identified as a novel prognostic biomarker in LUAD and targeting Siglec-15 may provide a promising strategy for LUAD immunotherapy.

Sublobectomy and lymph node sampling are adequate for patients with invasive lung adenocarcinoma presenting as pure ground glass nodules.

PURPOSE: In this study, we aimed to investigate the prognosis of invasive lung adenocarcinoma that manifests as pure ground glass nodules (pGGNs) and confirm the effectiveness of sublobectomy and lymph node sampling in patients with pGGN-featured invasive adenocarcinoma (IAC). MATERIALS AND METHODS: We retrospectively enrolled 139 patients with pGGN-featured IAC, who underwent complete resection in two medical institutions between January 2011 and May 2022. Stratification analysis was conducted to ensure balanced baseline characteristics among the patients. The 5-year overall survival (OS) and disease-free survival (DFS) rates were compared between the groups using Kaplan-Meier survival curves and log-rank test. RESULTS: The 5-year OS and DFS rates for patients with IAC presenting as pGGNs after surgery were 96.5% and 100%, respectively. No lymph node metastasis or recurrence was observed in any of the enrolled patients. There was no statistically significant difference in the 5-year OS between patients who underwent lobectomy or sublobectomy, along with lymph node resection or sampling. CONCLUSION: IAC presented as pGGNs exhibited low-grade malignancy and had a relatively good prognosis. Therefore, these patients may be treated with sublobectomy and lymph node sampling.

Integrated single-cell and bulk RNA-Seq analysis enhances prognostic accuracy of PD-1/PD-L1 immunotherapy response in lung adenocarcinoma through necroptotic anoikis gene signatures.

In addition to presenting significant diagnostic and treatment challenges, lung adenocarcinoma (LUAD) is the most common form of lung cancer. Using scRNA-Seq and bulk RNA-Seq data, we identify three genes referred to as HMR, FAM83A, and KRT6A these genes are related to necroptotic anoikis-related gene expression. Initial validation, conducted on the GSE50081 dataset, demonstrated the model's ability to categorize LUAD patients into high-risk and low-risk groups with significant survival differences. This model was further applied to predict responses to PD-1/PD-L1 blockade therapies, utilizing the IMvigor210 and GSE78220 cohorts, and showed strong correlation with patient outcomes, highlighting its potential in personalized immunotherapy. Further, LUAD cell lines were analyzed using quantitative PCR (qPCR) and Western blot analysis to confirm their expression levels, further corroborating the model's relevance in LUAD pathophysiology. The mutation landscape of these genes was also explored, revealing their broad implication in various cancer types through a pan-cancer analysis. The study also delved into molecular subclustering, revealing distinct expression profiles and associations with different survival outcomes, emphasizing the model's utility in precision oncology. Moreover, the diversity of immune cell infiltration, analyzed in relation to the necroptotic anoikis signature, suggested significant implications for immune evasion mechanisms in LUAD. While the findings present a promising stride towards personalized LUAD treatment, especially in immunotherapy, limitations such as the retrospective nature of the datasets and the need for larger sample sizes are acknowledged. Prospective clinical trials and further experimental research are essential to validate these findings and enhance the clinical applicability of our prognostic model.

GTSE1: A potential prognostic and diagnostic biomarker in various tumors including lung adenocarcinoma.

OBJECTIVE: This research was aimed to comprehensively investigate the expression levels, diagnostic and prognostic implications, and the relationship with immune infiltration of G2 and S phase-expressed-1 (GTSE1) across 33 tumor types, including lung adenocarcinoma (LUAD), through gene expression profiling. METHODS: GTSE1 mRNA expression data together with clinical information were acquired from Xena database of The Cancer Genome Atlas (TCGA), ArrayExpress, and Gene Expression Omnibus (GEO) database for this study. The Wilcoxon rank-sum test was used to detect differences in GTSE1 expression between groups. The ability of GTSE1 to accurately predict cancer status was evaluated by calculating the area under the curve (AUC) value for the receiver operating characteristic curve. Additionally, we investigated the predictive value of GTSE1 in individuals diagnosed with neoplasms using univariate Cox regression analysis as well as Kaplan-Meier curves. Furthermore, the correlation between GTSE1 expression and levels of immune infiltration was assessed by utilizing the Tumor Immune Estimate Resource (TIMER) database to calculate the Spearman rank correlation coefficient. Finally, the pan-cancer analysis findings were validated by examining the association between GTSE1 expression and prognosis among patients with LUAD. RESULTS: GTSE1 exhibited significantly increased expression levels in a wide range of tumor tissues in contrast with normal tissues (p < 0.05). The expression of GTSE1 in various tumors was associated with clinical features, overall survival, and disease-specific survival (p < 0.05). In immune infiltration analyses, a strong correlation of the level of immune infiltration with the expression of GTSE1 was observed. Furthermore, GTSE1 demonstrated good discriminative and diagnostic value for most tumors. Additional experiments confirmed the relationship between elevated GTSE1 expression and unfavorable prognosis in individuals diagnosed with LUAD. These findings indicated the crucial role of GTSE1 expression level in influencing the development and immune infiltration of different types of tumors. CONCLUSIONS: GTSE1 might be a potential biomarker for the prognosis of pan-cancer. Meanwhile, it represented a promising target for immunotherapy.

Integration of multi-omics data for survival prediction of lung adenocarcinoma.

BACKGROUND AND OBJECTIVE: The morbidity of lung adenocarcinoma (LUAD) has been increasing year by year and the prognosis is poor. This has prompted researchers to study the survival of LUAD patients to ensure that patients can be cured in time or survive after appropriate treatment. There is still no fully valid model that can be applied to clinical practice. METHODS: We introduced struc2vec-based multi-omics data integration (SBMOI), which could integrate gene expression, somatic mutations and clinical data to construct mutation gene vectors representing LUAD patient features. Based on the patient features, the random survival forest (RSF) model was used to predict the long- and short-term survival of LUAD patients. To further demonstrate the superiority of SBMOI, we simultaneously replaced scale-free gene co-expression network (FCN) with a protein-protein interaction (PPI) network and a significant co-expression network (SCN) to compare accuracy in predicting LUAD patient survival under the same conditions. RESULTS: Our results suggested that compared with SCN and PPI network, the FCN based SBMOI combined with RSF model had better performance in long- and short-term survival prediction tasks for LUAD patients. The AUC of 1-year, 5-year, and 10-year survival in the validation dataset were 0.791, 0.825, and 0.917, respectively. CONCLUSIONS: This study provided a powerful network-based method to multi-omics data integration. SBMOI combined with RSF successfully predicted long- and short-term survival of LUAD patients, especially with high accuracy on long-term survival. Besides, SBMOI algorithm has the potential to combine with other machine learning models to complete clustering or stratificational tasks, and being applied to other diseases.

Proteomic profiling of tumor microenvironment and prognosis risk prediction in stage I lung adenocarcinoma.

OBJECTIVES: With the increasing popularity of CT screening, more cases of early-stage lung cancer are being diagnosed. However, 24.5% of stage I non-small-cell lung cancer (NSCLC) patients still experience treatment failure post-surgery. Biomarkers to predict lung cancer patients at high risk of recurrence are needed. MATERIALS AND METHODS: We collected protein mass spectrometry data from the Taiwan Lung Cancer Moonshot Project and performed bioinformatics analysis on proteins with differential expressions between tumor and adjacent normal tissues in 74 stage I lung adenocarcinoma (LUAD) cases, aiming to explore the tumor microenvironment related prognostic biomarkers. Findings were further validated in 6 external cohorts. RESULTS: The analysis of differentially expressed proteins revealed that the most enriched categories of diseases and biological functions were cellular movement, immune cell trafficking, and cancer. Utilizing proteomic profiling of the tumor microenvironment, we identified five prognostic biomarkers (ADAM10, MIF, TEK, THBS2, MAOA). We then developed a risk score model, which independently predicted recurrence-free survival and overall survival in stage I LUAD. Patients with high risk scores experienced worse recurrence-free survival (adjusted hazard ratio = 8.28, p < 0.001) and overall survival (adjusted hazard ratio = 6.88, p = 0.013). Findings had been also validated in the external cohorts. CONCLUSION: The risk score model derived from proteomic profiling of tumor microenvironment can be used to predict recurrence risk and prognosis of stage I LUAD.

Deciphering the heterogeneity dominated by tumor-associated macrophages for survival prognostication and prediction of immunotherapy response in lung adenocarcinoma.

Tumor-associated macrophages (TAMs) are a specific subset of macrophages that reside inside the tumor microenvironment. The dynamic interplay between TAMs and tumor cells plays a crucial role in the treatment response and prognosis of lung adenocarcinoma (LUAD). The study aimed to examine the association between TAMs and LUAD to advance the development of targeted strategies and immunotherapeutic approaches for treating this type of lung cancer. The study employed single-cell mRNA sequencing data to characterize the immune cell composition of LUAD and delineate distinct subpopulations of TAMs. The "BayesPrism" and "Seurat" R packages were employed to examine the association between these subgroups and immunotherapy and clinical features to identify novel immunotherapy biomarkers. Furthermore, a predictive signature was generated to forecast patient prognosis by examining the gene expression profile of immunotherapy-associated TAMs subsets and using 104 machine-learning techniques. A comprehensive investigation has shown the existence of a hitherto unidentified subgroup of TAMs known as RGS1 + TAMs, which has been found to have a strong correlation with the efficacy of immunotherapy and the occurrence of tumor metastasis in LUAD patients. CD83 was identified CD83 as a distinct biomarker for the expression of RGS1 + TAMs, showcasing its potential utility as an indicator for immunotherapeutic interventions. Furthermore, the prognostic capacity of the RTMscore signature, encompassing three specific mRNA (NR4A2, MMP14, and NPC2), demonstrated enhanced robustness when contrasted against the comprehensive collection of 104 features outlined in the published study. CD83 has potential as an immunotherapeutic biomarker. Meanwhile, The RTMscore signature established in the present study might be beneficial for survival prognostication.

Prognostic Cell Death Index for Lung Adenocarcinoma: A Comprehensive Transcriptome-Based Analysis of Twelve Programmed Cell Death Pattern Genes.

OBJECTIVE: Lung adenocarcinoma (LUAD) is a prominent contributor to global cancer mortality, characterized by constrained prognosis. This study aimed to develop a novel prognostic indicator, the Cell Death Index (CDI), utilizing twelve programmed cell death (PCD) pattern genes, to predict the immune infiltration and prognosis in LUAD patients. METHODS: We collected PCD-related genes and identified prognostic PCD genes in the Cancer Genome Atlas (TCGA)-LUAD dataset, and made rigorous validation in the Clinical Proteomic Tumor Analysis Consortium (CPTAC)-LUAD cohorts. CDI was calculated using a multivariable Cox regression model. Functional enrichment and tumor microenvironment were evaluated. Drug sensitivity prediction and nomogram development were performed to assess CDI's potential value. RESULTS: The results revealed 10 PCD genes (ERO1A, CDK5R1, TRIM6, DNASE2B, ITPRIP, MRGPRX2, FGA, NDUFA13, NLRP2, and CD68) significantly associated with LUAD prognosis. The CDI was constructed and showed high accuracy in predicting patient survival with C-index values of 0.801 and 0.794 in the prognosis cohort and validation cohort, respectively. CDI is also indicative of variations in biological functions, tumor microenvironment, and immune cell infiltration including neutrophils, activated mast cells, activated dendritic cells, M0 macrophages, resting natural killer cells, γδT cells, and activated memory CD4+T cells. Furthermore, drug sensitivity analysis indicated potential targeted strategies. CONCLUSIONS: The CDI, based on PCD genes, serves as a robust prognostic tool for LUAD, offering profound insights into tumor biology, immune response, and personalized treatment strategies. This study underscores the pivotal role of PCD mechanisms in LUAD pathogenesis and identifies potential therapeutic targets.

Identifying an immunogenic cell death-related gene signature contributes to predicting prognosis, immunotherapy efficacy, and tumor microenvironment of lung adenocarcinoma.

BACKGROUND: Immunogenic cell death (ICD) is a regulated form of cell death that triggers an adaptive immune response. The objective of this study was to investigate the correlation between ICD-related genes (ICDGs) and the prognosis and the immune microenvironment of patients with lung adenocarcinoma (LUAD). METHODS: ICD-associated molecular subtypes were identified through consensus clustering. Subsequently, a prognostic risk model comprising 5 ICDGs was constructed using Lasso-Cox regression in the TCGA training cohort and further tested in the GEO cohort. Enriched pathways among the subtypes were analyzed using GO, KEGG, and GSVA. Furthermore, the immune microenvironment was assessed using ESTIMATE, CIBERSORT, and ssGSEA analyses. RESULTS: Consensus clustering divided LUAD patients into three ICDG subtypes with significant differences in prognosis and the immune microenvironment. A prognostic risk model was constructed based on 5 ICDGs and it was used to classify the patients into two risk groups; the high-risk group had poorer prognosis and an immunosuppressive microenvironment characterized by low immune score, low immune status, high abundance of immunosuppressive cells, and high expression of tumor purity. Cox regression, ROC curve analysis, and a nomogram indicated that the risk model was an independent prognostic factor. The five hub genes were verified by TCGA database, cell sublocalization immunofluorescence analysis, IHC images and qRT-PCR, which were consistent with bioinformatics analysis. CONCLUSIONS: The molecular subtypes and a risk model based on ICDGs proposed in our study are both promising prognostic classifications in LUAD, which may provide novel insights for developing accurate targeted cancer therapies.

Prognostic implications of combining EGFR-TKIs and radiotherapy in Stage IV lung adenocarcinoma with 19-Del or 21-L858R mutations: A real-world study.

OBJECTIVE: To elucidate the potential benefits of combining radiotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for individuals with Stage IV lung adenocarcinoma (LUAD) harboring either exon 19 deletion (19-Del) or exon 21 L858R mutation (21-L858R). METHODS: In this real-world retrospective study, 177 individuals with Stage IV LUAD who underwent EGFR-TKIs and radiotherapy at Shandong Cancer Hospital from June 2012 to August 2017 were included. The main focus of this real-world study was overall survival (OS). RESULTS: The clinical characteristics of patients with Stage IV LUAD harboring 19-Del were similar to those harboring 21-L858R (p > 0.05). Overall, the patients had a median OS (mOS) of 32.0 months (95% confidence interval [CI]: 28.6-35.5). Subsequently, multivariate analysis indicated that both EGFR mutations and thoracic radiotherapy were independent predictors of OS (p = 0.001 and 0.013). Furthermore, subgroup analysis highlighted a longer OS for the 19-Del group compared to the 21-L858R group, especially when EGFR-TKIs were combined with bone metastasis or thoracic radiotherapy (mOS: 34.7 vs. 25.1 months and 51.0 vs. 29.6 months; p = 0.0056 and 0.0013, respectively). However, no significant differences were found in OS when considering patients who underwent brain metastasis radiotherapy (mOS: 34.7 vs. 25.1 months; p = 0.088). CONCLUSIONS: Patients with Stage IV LUAD harboring 19-Del experience a notably prolonged OS following combined therapy with EGFR-TKIs and radiotherapy, while this OS benefit is observed despite the absence of substantial differences in the clinical characteristics between the 19-Del and 21-L858R groups.

Outcomes, responses, and prognostic analyses of intrathecal combined treatment for leptomeningeal metastasis from lung adenocarcinoma.

BACKGROUND: Leptomeningeal metastasis (LM) is a severe lung cancer complication, with potentially fatal consequences. The use of intrathecal therapy (IT) combined with systemic therapy has shown promise as a treatment approach for LM. Thus, this study aimed to evaluate the features and responses to IT combined therapy and identify determinants affecting patients with leptomeningeal metastasis resulting from lung adenocarcinoma (LM-LA). METHODS: A retrospective analysis of medical records from our hospital database was performed, covering from April 2018 to August 2022, for 37 patients diagnosed with LM-LA and treated with IT combined therapy. Patients who received IT combined therapy for LM-LA were evaluated for demographic characteristics, treatment efficacy, survival, and variables that impacted them. RESULTS: The median overall survival (mOS) of 37 patients was 16.0 months, and the survival rates at 6 and 12 months were 75.7% and 35.1%, respectively. Among the 21 patients with LM-LA who received IT combined with tyrosine kinase inhibitors (TKIs), the mOS was 17.0 months, which was significantly longer than that of patients treated with IT combined with chemotherapy (7.0 months, P = 0.010) and the best supportive care (6.0 months, P = 0.001). However, no significant survival benefit was observed in patients treated with IT combined with TKIs when compared with those treated with IT combined with PD-1 (5.0 months, P = 0.249). Multivariate analysis indicated that the combination of TKIs was an independent favorable prognostic factor for patients with LM-LA. CONCLUSION: Combination treatment is regarded as an additional option for patients with LM-LA. Compared with other combination therapies in our study, IT combined with TKI therapy provided a better survival outcome for patients with LM-LA.

Stem-like CD8 T cells in stage I lung adenocarcinoma as a prognostic biomarker: A preliminary study.

OBJECTIVES: This study aimed to investigate the presence of stem-like CD8 T (CD8 TSL) cells in lung adenocarcinoma (LUAD) and explore their relationships with the clinical outcomes. METHODS: Multiplex immunofluorescence (mIF) was performed to identify CD8 TSL and antigen-presenting cells (APC) in 76 LUAD patients. Differences in the number of CD8 TSL cells based on tumor stage and the spatial relationships between CD8 TSL cells and APC niches were determined. The optimal cutoff value of CD8 TSL cells for predicting survival in patients with stage I LUAD was calculated. RESULTS: CD8 TSL cells were present in all tumors, and their numbers were significantly higher in stage I patients than in stage III patients (P = 0.010); CD8 TSL cells located in the APC niches accounted for 69.7% (53/76) of the hotspot fields. The optimal cutoff value for the number of CD8 TSL cells required to predict the overall survival (OS) in patients with stage I LUAD was 2.5 per 10000 µm2. The median OS and progression-free survival (PFS) in the high-level group (>2.5) were significantly (P < 0.001) longer than those in the low-level group (≤2.5). The number of CD8 TSL cells was an independent prognostic factor for stage I LUAD. Patients with more CD8 TSL cells had a lower risk of death and disease progression than those with less CD8 TSL cells. CONCLUSION: CD8 TSL cells were observed in patients with stages I-III LUAD and might serve as prognostic biomarkers for stage I LUAD.

Prognostic and immunological implications of glutathione metabolism genes in lung adenocarcinoma: A focus on the core gene SMS and its impact on M2 macrophage polarization.

Glutathione metabolism (GM) is a crucial part of various metabolic and pathophysiological processes. However, its role in lung adenocarcinoma (LUAD) has not been comprehensively studied. This study aimed to explore the potential relationship between GM genes, the prognosis, and the immune microenvironment of patients with LUAD. We constructed a risk signature model containing seven GM genes using Lasso combined Cox regression and validated it using six GEO datasets. Our analysis showed that it is an independent prognostic factor. Functional enrichment analysis revealed that the GM genes were significantly enriched in cell proliferation, cell cycle regulation, and metabolic pathways. Clinical and gene expression data of patients with LUAD were obtained from the TCGA database and patients were divided into high- and low-risk groups. The high-risk patient group had a poor prognosis, reduced immune cell infiltration, poor response to immunotherapy, high sensitivity to chemotherapy, and low sensitivity to targeted therapy. Subsequently, single-cell transcriptome analysis using the GSE143423 and GSE127465 datasets revealed that the core SMS gene was highly enriched in M2 Macrophages. Finally, nine GEO datasets and multiple fluorescence staining revealed a correlation between the SMS expression and M2 macrophage polarization. Our prognostic model in which the core SMS gene is closely related to M2 macrophage polarization is expected to become a novel target and strategy for tumor therapy.

Disruptive and Truncating TP53 Mutations Are Associated with African-Ancestry and Worse Prognosis in Brazilian Patients with Lung Adenocarcinoma.

INTRODUCTION: TP53 is the most frequently mutated gene in lung tumors, but its prognostic role in admixed populations, such as Brazilians, remains unclear. In this study, we aimed to evaluate the frequency and clinicopathological impact of TP53 mutations in non-small cell lung cancer (NSCLC) patients in Brazil. METHODS: We analyzed 446 NSCLC patients from Barretos Cancer Hospital. TP53 mutational status was evaluated through targeted next-generation sequencing (NGS) and the variants were biologically classified as disruptive/nondisruptive and as truncating/nontruncating. We also assessed genetic ancestry using 46 ancestry-informative markers. Analysis of lung adenocarcinomas from the cBioportal dataset was performed. We further examined associations of TP53 mutations with patients' clinicopathological features. RESULTS: TP53 mutations were detected in 64.3% (n = 287/446) of NSCLC cases, with a prevalence of 60.4% (n = 221/366) in lung adenocarcinomas. TP53 mutations were associated with brain metastasis at diagnosis, tobacco consumption, and higher African ancestry. Disruptive and truncating mutations were associated with a younger age at diagnosis. Additionally, cBioportal dataset revealed that TP53 mutations were associated with younger age and Black skin color. Patients harboring disruptive/truncating TP53 mutations had worse overall survival than nondisruptive/nontruncating and wild-type patients. CONCLUSION: TP53 mutations are common in Brazilian lung adenocarcinomas, and their biological characterization as disruptive and truncating mutations is associated with African ancestry and shorter overall survival.

Identification and Validation of 7-lncRNA Signature of Epigenetic Disorders by Comprehensive Epigenetic Analysis.

The survival rate of patients with lung adenocarcinoma (LUAD) is low. This study analyzed the correlation between the expression of long noncoding RNA (lncRNA) and epigenetic alterations along with the investigation of the prognostic value of these outcomes for LUAD. Differentially expressed lncRNAs were identified based on multiomic data and positively related genes using DESeq2 in R, differentially histone-modifying genes specific to LUAD based on histone modification data, gene enhancers from information collected from the FANTOM5 (Function Annotation Of The Mammalian Genome-5) (fantom.gsc.riken.jp/5) human enhancer database, gene promoters using the ChIPseeker and the human lincRNAs Transcripts database in R, and differentially methylated regions (DMRs) using Bumphunter in R. Overall survival was estimated by Kaplan-Meier, comparisons were performed among groups using log-rank tests to derive differences between sample subclasses, and epigenetic lncRNAs (epi-lncRNAs) potentially relevant to LUAD prognosis were identified. A total of seven dysregulated epi-lncRNAs in LUAD were identified by comparing histone modifications and alterations in histone methylation regions on lncRNA promoter and enhancer elements, including H3K4me2, H3K27me3, H3K4me1, H3K9me3, H4K20me1, H3K9ac, H3K79me2, H3K27ac, H3K4me3, and H3K36me3. Furthermore, 69 LUAD-specific dysregulated epi-lncRNAs were identified. Moreover, lncRNAs-based prognostic analysis of LUAD samples was performed and explored that seven of these lncRNAs, including A2M-AS1, AL161431.1, DDX11-AS1, FAM83A-AS1, MHENCR, MNX1-AS1, and NKILA (7-EpiLncRNA), showed the potential to serve as markers for LUAD prognosis. Additionally, patients having a high 7-EpiLncRNA score showed a generally more unfavorable prognosis compared with those which scored lower. Seven lncRNAs were identified as markers of prognosis in patients with LUAD. The outcomes of this research will help us understand epigenetically aberrant regulation of lncRNA expression in LUAD in a better way and have implications for research advances in the regulatory role of lncRNAs in LUAD.

A Novel Predictive Model Incorporating Ferroptosis-Related Gene Signatures for Overall Survival in Patients with Lung Adenocarcinoma.

BACKGROUND Lung adenocarcinoma (LUAD) is the predominant histological type of lung cancer with high morbidity and mortality. Ferroptosis is regarded as a new pattern of programmed cell death concerned with the progression of lung cancer characterized by lipid peroxidation. Nevertheless, the prognostic role of ferroptosis-related genes for LUAD warrant to be explored. MATERIAL AND METHODS RNA sequencing and relevant clinical patient data were obtained from public-access databanks. A prognostic model was constructed through the LASSO Cox regression in the cancer genome atlas cohort. The diagnostic value of the prognostic model was further evaluated in the gene expression omnibus cohort. RESULTS Most of the ferroptosis-related genes (69.9%) were differentially expressed between tumor and adjacent non-cancerous tissues. 43 differentially expressed genes showed a close association with the prognosis of LUAD patients (adjusted p-value <0.05). An 18-gene signature was built and applied to assign patients into high vs low-risk groups. Compared with the high-risk group, patients defined as the low-risk group suffered significantly prolonged OS. Both uni- and multivariate analyses demonstrated that the signature-based score served as a crucial role in influencing the OS of LUAD patients (hazard ratio >1, p<0.001). The immunity-related signaling pathway was enriched in the functional analysis and the infiltration of the immune cells showed a great difference between groups. CONCLUSIONS The predictive model could be applied for prognostic prediction for LUAD. Targeting ferroptosis could be a possible curative strategy against LUAD, and immunomodulation may be one of the potential mechanisms.

An integrated analysis of the competing endogenous RNA network associated of prognosis of stage I lung adenocarcinoma.

BACKGROUND: Accumulating evidence indicates that long non-coding RNAs (lncRNAs) are involving in the tumorigenesis and metastasis of lung cancer. The aim of the study is to systematically characterize the lncRNA-associated competing endogenous RNA (ceRNA) network and identify key lncRNAs in the development of stage I lung adenocarcinoma (LUAD). METHODS: Totally, 1,955 DEmRNAs, 165 DEmiRNAs and 1,107 DElncRNAs were obtained in 10 paired normal and LUAD tissues. And a total of 8,912 paired lncRNA-miRNA-mRNA network was constructed. Using the Cancer Genome Atlas (TCGA) dataset, the module of ME turquoise was revealed to be most relevant to the progression of LUAD though Weighted Gene Co-expression Network Analysis (WGCNA). RESULTS: Of the lncRNAs identified, LINC00639, RP4-676L2.1 and FENDRR were in ceRNA network established by our RNA-sequencing dataset. Using univariate Cox regression analysis, FENDRR was a risk factor of progression free survival (PFS) of stage I LUAD patients (HRs = 1.69, 95%CI 1.07-2.68, P < .050). Subsequently, diffe rential expression of FENDRR in paired normal and LUAD tissues was detected significant by real-time quantitative (qRT-PCR) (P < 0.001). CONCLUSIONS: This study, for the first time, deciphered the regulatory role of FENDRR/miR-6815-5p axis in the progression of early-stage LUAD, which is needed to be established in vitro and in vivo.

Expression and prognostic impact of CD49b in human lung cancer.

ABSTRACT: Lung cancer remains the worldwide leading cause of cancer-related death. Currently, prognostic biomarkers for the detection and stratification of lung cancer are being investigated for clinical use. The surface protein cluster of differentiation 49b (CD49b) plays an important role in promoting cell proliferation and invasion in different tumor entities and blocking CD49b improved the tumor immune response. Overexpression of CD49b has been associated with unfavorable survival rates in several malignant tumor entities, such as prostate cancer, gastric cancer and colon cancer. Therefore, we aimed to analyze the protein expression of CD49b in patients with different types of lung cancer and additionally to identify the influence of CD49b on clinicopathological characteristics and overall survival.Expression levels of CD49b were retrospective analyzed by immunohistochemistry in 92 cases of pulmonary adenocarcinoma (AC), 85 cases of squamous cell lung carcinoma (SQCLC) and 32 cases of small cell lung cancer (SCLC) and correlated with clinicopathological characteristics and patients' overall survival.A strong expression of CD49b was most seen in SQCLC (78%), followed by AC (48%) and SCLC (9%). All patients combined, strong expression of CD49b correlated significantly with poorer overall survival. However, an increased expression of CD49b correlated significantly with a poorer survival rate only in SQCLC. In AC and SCLC, no significant correlation could be demonstrated in this regard.In our study, CD49b expression was associated with poor overall survival in patients with SQCLC. Accordingly, CD49b could serve as a new prognostic biomarker and, moreover, be a potential new drug target in SQCLC.

The RNA editing enzyme ADAR modulated by the rs1127317 genetic variant diminishes EGFR-TKIs efficiency in advanced lung adenocarcinoma.

AIMS: The adenosine-to-inosine (A-to-I) RNA editing controlled by the editing genes are known to diversify transcripts in human. Aberrant A-to-I editing due to dysregulation of the editing genes are involved in cancer development. However, it is still largely unclear how single nucleotide polymorphisms (SNPs) in the A-to-I editing genes confer to recurrence and/or drug resistance of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) therapy in non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: In this study, we systematically evaluated and validated the role of twenty-eight potential functional genetic variants in four A-to-I editing genes (ADAR, ADARB1, ADARB2 and AIMP2) in prognosis of NSCLC patients receiving EGFR-TKIs. KEY FINDINGS: We identified the ADAR rs1127309, rs1127317, and rs2229857 SNPs markedly contributing to prognosis of patients treated with EGFR-TKIs. Interestingly, SNP rs1127317 locating in the ADAR 3'-untranslated region regulates gene expression in an allele-specific manner via modulating binding of miR-454-5p in cells. In support of this, patients with the rs1127317 C allele correlated with elevated ADAR expression in tumors showed profoundly shorten survival after EGFR-TKIs therapy compared to the A allele carriers. Silencing of ADAR notably enhanced gefitinib sensitivities of NSCLC cells. SIGNIFICANCE: Our findings highlight the importance of the A-to-I RNA editing in drug resistance and nominate ADAR as a potential therapeutic target for unresectable NSCLC.