Factor For Lung Adenocarcinoma Patients Research Articles

Neutrophil in the suppressed immune microenvironment: Critical prognostic factor for lung adenocarcinoma patients with KEAP1 mutation.

It is still unclear whether KEAP1 mutation is detrimental to immunotherapy of lung adenocarcinoma (LUAD) patients, we try to analyse the exact changes in the TME in LUAD patients with KEAP1 mutations and to identify key factors influencing prognosis. A total of 1,029 patients with lung squamous carcinoma (LUSC) or LUAD with data obtained from The Cancer Genome Atlas were included in this study. The TME and OS of patients with LUAD stratified by mutant versus wild-type KEAP1 status were comprehensively measured. Moreover, we classified LUAD patients with KEAP1 mutations into three subtypes, by unsupervised consensus clustering. We further analysed the TME, OS, commutated genes and metabolic pathways of different subgroups. A total of 40 LUAD patients underwent immunotherapy were collected and classified into mutant KEAP1 group and wild-type KEAP1 group. We also conducted immunohistochemical staining in KEAP1-MT groups. Suppressed TME was observed not only in LUAD patients but also in LUSC patients. LUAD patients with mutant KEAP1 underwent immunotherapy had worse PFS than wild-type KEAP1. Unsupervised consensus clustering analysis suggested that the three subtypes of patients exhibited different densities of neutrophil infiltration and had different OS results: cluster 2 patients had significantly higher levels of neutrophils had significantly worse prognoses than those of patients in clusters 1 and 3 and patients with wild-type KEAP1. Univariate and multivariate Cox analyses proved that a high density of neutrophils was significantly associated with worse OS and immunohistochemical staining proved that shorter PFS showed high density of neutrophils. KEAP1 mutation significantly suppresses the tumour immune microenvironment in LUAD patients. LUAD patients with mutant KEAP1 underwent immunotherapy had worse PFS than with wild-type KEAP1. Neutrophils may play an important role in the prognosis of LUAD patients with KEAP1 mutations and may provide a promising therapeutic target.

Comprehensive genomic and clinical analyses identify APOBEC mutational signatures as a brain metastasis risk factor in lung adenocarcinoma patients

BackgroundLung adenocarcinoma is the most common source of brain metastasis (BM), resulting in significant morbidity and mortality. We aimed to identify patients with high BM risk who possibly benefit from brain-penetrant drugs, prophylactic cranial irradiation, or close brain magnetic resonance imaging surveillance. MethodsMetastatic lung adenocarcinoma patients with extracranial tumor samples profiled by a next-generation sequencing panel targeting 425 tumor-related genes were retrospectively enrolled between February 2008 and July 2021. We compared BM and non-BM patients’ genomic and clinical features and studied their associations with BM risk. Two external cohorts were used for result validation and molecular mechanisms investigation, respectively. ResultsWe included 174 eligible patients, including 90 having developed BM by the end of follow-up. Age≤60, EGFR activating mutations, and high-level apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) mutational signatures were associated with elevated BM risk. Similar findings in BM-free survival were obtained by fitting Fine-Gray subdistribution hazard models addressing competing risks. Increased BM risk related to APOBEC mutational signatures was validated in an external cohort (N = 440). RNA sequencing data analyses performed in another external cohort (N = 230) revealed that expressions of metastasis-related pathways such as transforming growth factor (TGF)β and epithelial-mesenchymal transition (EMT) were upregulated in the patients with high-level APOBEC mutational signatures. ConclusionAPOBEC mutational signatures related to upregulated TGFβ and EMT, could serve as an independent risk factor for BM and BM-free survival in metastatic lung adenocarcinoma patients. Further investigations are warranted to tailor personalized treatments to improve the susceptible patient's outcomes.

Identification of CDT1 as a prognostic marker in human lung adenocarcinoma using bioinformatics approaches.

Lung cancer has the highest cancer-related mortality worldwide. Lung adenocarcinoma (LUAD) is the most common histological subtype of non-small cell lung cancer (NSCLC). Chromatin licensing and DNA replication factor 1 (CDT1), a key regulator of cell cycle control and replication in eukaryotic cells, has been implicated in various cancer-related processes. Given its significant role in cancer, the focus on CDT1 in this study is justified as it holds promise as a potential biomarker or therapeutic target for cancer treatment. However, its prognostic value in lung adenocarcinoma (LUAD) remains unclear. Bioinformatics analysis was conducted using data obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were utilized to predict biological processes and signaling pathways, respectively. The LinkedOmics database was employed to identify differentially expressed genes (DEGs) associated with CDT1. Nomograms and Kaplan-Meier plots were generated to assess the survival rates of patients with lung adenocarcinoma (LUAD). To determine the RNA and protein expression levels of CDT1 in LUAD and adjacent normal tissues, quantitative polymerase chain reaction (qPCR) and immunohistochemistry techniques were employed, respectively. CDT1 was upregulated in the vast majority of cancer tissues, based on pan-cancer analysis in TCGA and GEO datasets, as to lung cancer, the level of CDT1 expression was much higher in LUAD tissue than in healthy lung tissue. Our clinical data supported these findings. In our study, we used a specific cutoff value to dichotomize the patient samples into high and low CDT1 expression groups. The Kaplan-Meier survival curve revealed poor survival rates in CDT1 high expression group than the low expression group. To determine if CDT1 expression was an independent risk factor in LUAD patients, univariate and multivariate Cox regression analyses were performed. The result showed that CDT1 was a potential novel prognosis factor for LUAD patients, whose prognosis was poorer when CDT1 expression was higher. Based on functional enrichment analysis, highly expressed DEGs of CDT1-high patients were predicted to be involved in the cell cycle. According to our analysis of immune infiltration, CDT1 exhibited a strong correlation with specific immune cell subsets and was found to be a significant predictor of poor survival in patients with LUAD. Our research found that CDT1 was upregulated in LUAD and that high CDT1 expression predicted poor prognosis. We comprehensively and systematically analyzed the expression level in the datasets as well as in our own clinical samples, we also evaluated the prognostic and diagnostic value of CDT1, and finally, the potential mechanisms of CDT1 in the progression of LUAD. These results suggested that CDT1 may be a prognostic marker and therapeutic target for LUAD.

Construction and validation of a novel prognostic nomogram for predicting overall survival in lung adenocarcinoma patients with different patterns of metastasis

ObjectiveMetastasis of lung cancer is an important factor affecting survival. The present study proposed to establish and verify a nomogram for predicting overall survival (OS) in lung adenocarcinoma (LUAD) patients with different patterns of metastasis.MethodsA total of 9727 patients diagnosed with metastatic LUAD patients from 2010 to 2015 were enrolled based on surveillance, epidemiology and end results (SEER) Database and then randomly divided into training and validation cohorts, and 136 patients in our Cancer Center were enrolled as the external validation cohort. Univariate and multivariate analyses were performed to evaluate the prognostic impact on OS. A prognostic nomogram was constructed and evaluated by C-index, calibration curve, decision curve analysis (DCA), and risk stratification system.ResultsUltimately, 6809 and 2918 patients diagnosed with metastatic LUAD in the training and validation cohorts were enrolled in the study, respectively. A male sex, a later T and N stage, a larger tumor size, treatment including no surgery, no chemotherapy and no radiotherapy, metastasis sites were found to be independent risk factors in LUAD patients for worse OS, and then incorporated into the nomogram. The frequency of bone metastasis was the highest, and in single site metastasis, the prognosis of liver metastasis was the worst. Two-site metastasis is more common than three-site and four-site metastasis, and co-metastasis eventually leads to a worse survival outcome. The C-index value of nomogram for predicting OS were 0.798, 0.703 and 0.698 in the internal training, validation and external validation cohorts, separately. The calibration curves for the 6-months, 1-year and 2-year showed significant agreement between nomogram models and actual observations. The DCA curves indicated nomogram was more beneficial than the AJCC TNM stage. Patients were further divided into low-risk and high-risk groups according to nomogram predicted scores and developed a survival risk classification system.ConclusionsOur prognostic nomogram is expected to be an accurate and individualized clinical predictive tool for predicting OS in LUAD patients with different patterns of metastasis.

The hypoxia-associated genes in immune infiltration and treatment options of lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a common lung cancer with a poor prognosis under standard chemotherapy. Hypoxia is a crucial factor in the development of solid tumors, and hypoxia-related genes (HRGs) are closely associated with the proliferation of LUAD cells. In this study, LUAD HRGs were screened, and bioinformatics analysis and experimental validation were conducted. The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases were used to gather LUAD RNA-seq data and accompanying clinical information. LUAD subtypes were identified by unsupervised cluster analysis, and immune infiltration analysis of subtypes was conducted by GSVA and ssGSEA. Cox regression and LASSO regression analyses were used to obtain prognosis-related HRGs. Prognostic analysis was used to evaluate HRGs. Differences in enrichment pathways and immunotherapy were observed between risk groups based on GSEA and the TIDE method. Finally, RT-PCR and in vitro experiments were used to confirm prognosis-related HRG expression in LUAD cells. Two hypoxia-associated subtypes of LUAD were distinguished, demonstrating significant differences in prognostic analysis and immunological characteristics between subtypes. A prognostic model based on six HRGs (HK1, PDK3, PFKL, SLC2A1, STC1, and XPNPEP1) was developed for LUAD. HK1, SLC2A1, STC1, and XPNPEP1 were found to be risk factors for LUAD. PDK3 and PFKL were protective factors in LUAD patients. This study demonstrates the effect of hypoxia-associated genes on immune infiltration in LUAD and provides options for immunotherapy and therapeutic strategies in LUAD.

Intrinsic Immunogenic Tumor Cell Death Subtypes Delineate Prognosis and Responsiveness to Immunotherapy in Lung Adenocarcinoma.

Recent studies have highlighted the combination of activation of host immunogenic cell death (ICD) and tumor-directed cytotoxic strategies. However, overall multiomic analysis of the intrinsic ICD property in lung adenocarcinoma (LUAD) has not been performed. Therefore, the aim of this study was to develop an ICD-based risk scoring system to predict overall survival (OS) and immunotherapeutic efficacy in patients. In our study, both weighted gene co-expression network analysis (WGCNA) and LASSO-Cox analysis were utilized to identify ICDrisk subtypes (ICDrisk). Moreover, we identify genomic alterations and differences in biological processes, analyze the immune microenvironment, and predict the response to immunotherapy in patients with pan-cancer. Importantly, immunogenicity subgroup typing was performed based on the immune score (IS) and microenvironmental tumor neoantigens (meTNAs). Our results demonstrate that ICDrisk subtypes were identified based on 16 genes. Furthermore, high ICDrisk was proved to be a poor prognostic factor in LUAD patients and indicated poor efficacy of immune checkpoint inhibitor (ICI) treatment in patients with pan-cancer. The two ICDrisk subtypes displayed distinct clinicopathologic features, tumor-infiltrating immune cell patterns, and biological processes. The ISlowmeTNAhigh subtype showed low intratumoral heterogeneity (ITH) and immune-activated phenotypes and correlated with better survival than the other subtypes within the high ICDrisk group. This study suggests effective biomarkers for the prediction of OS in LUAD patients and immunotherapeutic response across Pan-cancer and contributes to enhancing our understanding of intrinsic immunogenic tumor cell death.

MRPL12 Acts as A Novel Prognostic Biomarker Involved in Immune Cell Infiltration and Tumor Progression of Lung Adenocarcinoma.

Mitochondrial ribosomal protein L7/L12 (MRPL12) is a member of the mitochondrial ribosomal proteins (MRPs). However, the biological function of MRPL12 in lung adenocarcinoma (LUAD) remains unclear. The expression and prognostic value of MRPL12 in LUAD were systematically analyzed using UALCAN, TIMER, HPA, Kaplan-Meier plotter, and GEPIA databases. The relationship between MRPL12 and immune infiltrates was investigated using TIMER and TISIDB databases. The clinical significance of MRPL12 in LUAD patients was validated using a tissue microarray (TMA). Cellular functional experiments were carried out to examine the influences of MRPL12 knockdown on cell proliferation, migration, and invasion. MRPL12 was significantly upregulated in LUAD samples, and high MRPL12 expression was correlated with worse prognosis. MRPL12 expression was markedly associated with immunomodulators, chemokines, and infiltration levels of multiple immune cells. Furthermore, TMA results confirm the upregulation of MRPL12 expression in LUAD, and MRPL12 was identified as an independent prognostic factor in LUAD patients. MRPL12 knockdown inhibited proliferation, migration, and invasion of LUAD cells. These data indicate that MRPL12 is a prognostic biomarker and correlated with immune infiltrates in LUAD. Therefore, MRPL12 shows potential as a therapeutic target for LUAD.

Human Papillomavirus Oncoproteins Confer Sensitivity to Cisplatin by Interfering with Epidermal Growth Factor Receptor Nuclear Trafficking Related to More Favorable Clinical Survival Outcomes in Non-Small Cell Lung Cancer.

High-risk human papillomavirus (HPV) infections and epidermal growth factor receptor (EGFR) expression have been reported to be associated with more favorable survival outcomes in lung adenocarcinoma patients. In this study, we utilized transfected HPV 16E5/16E6/16E7 H292 cells to investigate the mechanism of HPV oncoproteins interfering with EGFR nuclear trafficking related to a better response to cisplatin. Furthermore, we correlated HPV 16E6/18E6 expression and differentially localized EGFR expression with the clinical association and survival impact in lung adenocarcinoma patients. Our results found significantly higher phosphorylated nuclear EGFR expression upon epidermal growth factor stimulus and better responses to cisplatin in transfected HPV 16E5/16E6/16E7 NCI-H292 cells and xenograft animal models. Our data were compatible with clinical results of a high correlation of HPV 16E6/18E6 and EGFR expression in non-small cell lung cancer tissues and the synergistic effects of both with the best survival prognosis in a lung adenocarcinoma cohort, especially in patients with older age, no brain metastasis, smoking history, and wild-type EGFR status. Cumulatively, our study supports HPV 16E5/16E6/16E7 oncoproteins interfering with EGFR nuclear trafficking, resulting in increased sensitivity to cisplatin. HPV 16E6/18E6 and EGFR expression serve as good prognostic factors in lung adenocarcinoma patients.

12P The efficacy of EGFR tyrosine kinase inhibitors and its clinical prognostic factors in lung adenocarcinoma patients harboring different types of EGFR mutations: Real-world data

Lung cancer has the highest incidence and mortality among all cancers, with a 5-year survival rate of 15%. Presently, epidermal growth factor receptor (EGFR) mutation is the most common type of gene mutations detected in patients (pts) with advanced non-small-cell lung cancer, and EGFR is identified as the therapeutic target of EGFR tyrosine kinase inhibitors (TKIs). EGFR-TKIs have become the standard treatment. However, the most of the trials were developed in Asian countries, with a lack of data in western population.

A Two-eRNA-Based Signature Can Impact the Immune Status and Predict the Prognosis and Drug Sensitivity of Lung Adenocarcinoma.

Enhancer RNAs (eRNAs) are intergenic long noncoding RNAs (lncRNAs) participating in the development of malignant cancers via targeting cancer-associated genes and immune checkpoints. Immune infiltration of the tumor microenvironment was positively associated with overall survival (OS) in lung adenocarcinoma (LUAD). In this study, we aimed to explore the clinical significance of PCBP1-AS1 in LUAD and developed a novel prognostic signature based on two eRNAs. Our team discovered that the expression of PCBP1-AS1 was distinctly downregulated in LUAD specimens compared with nontumor specimens. Lower PCBP1-AS1 expression was related to advanced clinical stages and poor prognosis. KEGG analysis unveiled that the coexpression genes of PCBP1-AS1 were involved in the regulation of several tumor-related pathways. In addition, remarkable associations were observed between the expression of PCBP1-AS1 and the levels of several immune cells. Then, we used PCBP1-AS1 and TBX5-AS1 to develop a prognostic model. Survival assays unveiled that patients with higher risk scores exhibited a shorter OS in contrast to patients with lower risk scores. In addition, multivariable Cox regressive analysis indicated that the risk score was an independent prediction factor in LUAD sufferers. The anticancer drug sensitivity analysis indicated that risk score had a positive relationship with several anticancer drugs. Taken together, our findings indicated PCBP1-AS1 as a function modulator in LUAD development. In addition, we constructed a robust immune-related eRNA signature which might be a clinical prognosis factor for LUAD patients.

Identification of the Signature Genes and Network of Reactive Oxygen Species Related Genes and DNA Repair Genes in Lung Adenocarcinoma.

Reactive Oxygen Species (ROS) are present in excess amounts in patients with tumors, and these ROS can kill and destroy tumor cells. Therefore, tumor cells upregulate ROS-related genes to protect them and reduce their destructing effects. Cancer cells already damaged by ROS can be repaired by expressing DNA repair genes consequently promoting their proliferation. The present study aimed to identify the signature genes of and regulating network of ROS-related genes and DNA repair genes in lung adenocarcinoma (LUAD) using transcriptomic data of public databases. The LUAD transcriptome data in the TCGA database and gene expressions from Gene Expression Omnibus (GEO) were analyzed and samples were clustered into 5 ROS-related categories and 6 DNA repair categories. Survival analysis revealed a significant difference in patient survival between the two classification methods. In addition, the samples corresponding to the two categories overlap, thus, the gene expression profile of the same sample with different categories and survival prognosis was further explored, and the connection between ROS-related and DNA repair genes was investigated. The interactive sample recombination classification was used, revealing that the patient's prognosis was worse when the ROS-related and DNA repair genes were expressed at the same time. The further research on the potential regulatory network of the two categories of genes and the correlation analysis revealed that ROS-related genes and DNA repair genes have a mutual regulatory relationship. The ROS-related genes namely NQO1, TXNRD1, and PRDX4 could establish links with other DNA repair genes through the DNA repair gene NEIL3, thereby balancing the level of ROS. Therefore, targeting ROS-related genes and DNA repair genes might be a promising strategy in the treatment of LUAD. Finally, a survival prognostic model of ROS-related genes and DNA repair genes was established (TERT, PRKDC, PTTG1, SMUG1, TXNRD1, CAT, H2AFX, and PFKP). The risk score obtained from our survival prognostic model could be used as an independent prognostic factor in LUAD patients.

Effect of WW Domain-Containing Oxidoreductase Gene Polymorphism on Clinicopathological Characteristics of Patients with EGFR Mutant Lung Adenocarcinoma in Taiwan.

Lung adenocarcinoma is the most common histological type of non-small cell lung cancer, which accounts for the majority of lung cancers. Previous studies have showed that dysregulation of WW domain-containing oxidoreductase (WWOX) participates in the generation of several cancer types, including lung cancer. However, whether these WWOX polymorphisms are related to the clinical risk of epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma is worthy of investigation. The present study examined the relationship between the WWOX single-nucleotide polymorphisms (SNPs; rs11545028, rs12918952, rs3764340, rs73569323, and rs383362) and the clinicopathological factors in lung adenocarcinoma patients with or without EGFR mutations. We found that there was no significant difference in the genotype distribution of WWOX polymorphism between EGFR wild-type and EGFR mutant in patients with lung adenocarcinoma. Our results demonstrated that the presence of at least one G genotype (CG and GG) allele on WWOX rs3764340 was associated with a significantly higher risk of nearby lymph node involvement in those patients harboring EGFR mutations (odds ratio (OR) = 3.881, p = 0.010) compared with the CC genotype. Furthermore, in the subgroup of lung adenocarcinoma patients with the EGFR-L858R mutation, both WWOX rs3764340 C/G (OR = 5.209, p = 0.023) and rs73569323 C/T polymorphisms (OR = 3.886, p = 0.039) exhibited significant associations with the size of primary tumors and the invasion of adjacent tissues. In conclusion, these data indicate that WWOX SNPs may help predict tumor growth and invasion in patients with EGFR mutant lung adenocarcinoma, especially those with the EGFR-L858R mutant in Taiwan.

Systematic Analyses of a Chemokine Family-Based Risk Model Predicting Clinical Outcome and Immunotherapy Response in Lung Adenocarcinoma

Chemokines exhibited complicated functions in antitumor immunity, with their expression profile and clinical importance of lung adenocarcinoma (LUAD) patients remaining largely undetermined. This study aimed to explore the expression patterns of chemokine family in LUAD and construct a predictive chemokine family-based signature. A total of 497 samples were downloaded from the Cancer Genome Atlas (TCGA) data portal as the training set, and the combination of 4 representative Gene Expression Omnibus (GEO) datasets, including GSE30219, GSE50081, GSE37745, and GSE31210, were utilized as the validation set. A three gene-based signature was constructed using univariate and stepwise multivariate Cox regression analysis, classifying patients into high and low risk groups according to the overall survival. The independent GEO datasets were utilized to validate this signature. Another multivariate analysis revealed that this signature remained an independent prognostic factor in LUAD patients. Furthermore, patients in the low risk group featured immunoactive tumor microenvironment (TME), higher IPS scores and lower TIDE scores, and was regarded as the potential beneficiaries of immunotherapy. Finally, the role of risky CCL20 was validated by immunohistochemistry (IHC), and patients possessed higher CCL20 expression presented shorter overall survival (P = 0.011).

Identifying Common Genes Related to Platelet and Immunity for Lung Adenocarcinoma Prognosis Prediction.

BackgroundAlthough 1000s of immune-related and platelet receptor-related genes have been identified in lung adenocarcinoma, their role in prognosis prediction remains unclear.MethodsWe downloaded mRNA data from the Cancer Genome Atlas Dataset (TCGA), and GSE68465 or GSE14814 data sets from the Gene Expression Omnibus (GEO) database.ResultsThe high-risk group’s overall survival (OS) time was lower than that of the low-risk group’s in TCGA (p = 1.15e-03). Additionally, the risk score was an independent prognostic survival factor for lung adenocarcinoma patients in TCGA (HR = 2.136, 95%CI = 1.553–2.937, p < 0.001). The model’s prognostic performance was verified with two independent GEO cohorts (GSE68465 and GSE14814). We also developed a nomogram and provided free webpage prediction tools.1 The mechanism of the high-risk group in this risk score may be have been related to somatic mutations and copy number changes. In addition, this risk score can distinguish the prognosis of the other two cancers (ACC, p < 0.001 and KIRP, p < 0.001). Also, among the other seven cancers, the OS prognosis for high and low risk groups show wide variation (p < 0.05).ConclusionOur research demonstrates that CCNA2 and TGFB2 are potential diagnostic and prognostic biomarkers, as well as therapeutic targets in lung adenocarcinoma (LUAD). We also determined a novel and reliable prognostic score for lung adenocarcinoma prognosis. The online nomogram prediction tool that contains this risk score may also help clinical medical staff.

Bilirubin Can Be Used as a Prognostic Factor for Lung Adenocarcinoma Patients with EGFR Mutations.

Background and ObjectivesNon-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) mutation demonstrate only a median progression-free survival (PFS) of 8 to 10 months and undergo EGFR tyrosine kinase inhibitors (EGFR-TKIs) therapy. For decades, bilirubin has been reported to be associated with the onset and prognosis of lung cancer as a prooxidant. This study aimed to investigate the prediction of pretreatment circulating bilirubin for PFS in lung adenocarcinoma (LAC) patients who underwent EGFR-TKIs targeted therapy.Patients and MethodsLAC cases diagnosed and undergone EGFR-TKIs targeted therapy at The First Affiliated Hospital of Zhengzhou University between 2013 and 2015 were retrospectively reviewed. A total of 180 patients were studied according to inclusion and exclusion criteria. Follow-up data were collected for all patients until the disease progressed.ResultsUnivariate analysis showed that the levels of pretreatment total bilirubin (TBIL), indirect bilirubin (IBIL) and direct bilirubin (DBIL) were related to PFS (all p<0.05). Considering the close relationship among the three factors, we combined TBIL, IBIL and DBIL into one total factor, which is called bilirubin. Kaplan–Meier survival curves and Log rank tests indicated that patients with lower bilirubin levels had a shorter median PFS than those with higher bilirubin levels (8 vs. 15 months; p=0.002). Multivariate analysis demonstrated that pretreatment bilirubin is an independent prognostic factor (HR=0.454, CI: 0.267–0.773, p=0.004).ConclusionThis study confirms that bilirubin can predict the prognosis of LAC patients who had undergone EGFR-TKIs targeted therapy.

Identification and validation of smoking-related genes in lung adenocarcinoma using an in vitro carcinogenesis model and bioinformatics analysis

BackgroundLung cancer is one of the most common carcinomas in the world, and lung adenocarcinoma (LUAD) is the most lethal and most common subtype of lung cancer. Cigarette smoking is the most leading risk factor of lung cancer, but it is still unclear how normal lung cells become cancerous in cigarette smokers. This study aims to identify potential smoking-related biomarkers associated with the progression and prognosis of LUAD, as well as their regulation mechanism using an in vitro carcinogenesis model and bioinformatics analysis.ResultsBased on the integration analysis of four Gene Expression Omnibus (GEO) datasets and our mRNA sequencing analysis, 2 up-regulated and 11 down-regulated genes were identified in both S30 cells and LUAD. By analyzing the LUAD dataset in The Cancer Gene Analysis (TCGA) database, 3 of the 13 genes, viz., glycophorin C (GYPC), NME/NM23 nucleoside diphosphate kinase 1 (NME1) and slit guidance ligand 2 (SLIT2), were found to be significantly correlated with LUAD patients’ smoking history. The expression levels of GYPC, NME1 and SLIT2 in S30 cells and lung cancer cell lines were validated by quantitative PCR, immunofluorescence, and western blot assays. Besides, these three genes are associated with tumor invasion depth, and elevated expression of NME1 was correlated with lymph node metastasis. The enrichment analysis suggested that these genes were highly correlated to tumorigenesis and metastasis-related biological processes and pathways. Moreover, the increased expression levels of GYPC and SLIT2, as well as decreased expression of NME1 were associated with a favorable prognosis in LUAD patients. Furthermore, based on the multi-omics data in the TCGA database, these genes were found to be regulated by DNA methylation.ConclusionIn conclusion, our observations indicated that the differential expression of GYPC, NME1 and SLIT2 may be regulated by DNA methylation, and they are associated with cigarette smoke-induced LUAD, as well as serve as prognostic factors in LUAD patients.

Prognostic value of TP53 co-mutation status combined with EGFR mutation in patients with lung adenocarcinoma.

TP53/EGFR co-mutation has been reported to affect the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma (LUAD). However, its impact on survival is unclear. In this analysis, we explored the prognostic effect of TP53/EGFR co-mutation in LUAD. Clinical data and transcriptome sequencing of LUAD patients with matched genomic data were downloaded from the Cancer Genome Atlas (TCGA) database for overall survival (OS) analysis. Differential expression genes (DEGs) were recognized by R software and bioconductor package. Clusterprofiler was used for functionalanalysis. STRING was used for estimating PPI information and plug-in CytoHubba to screen hub modules in Cytoscape.The association between tumor mutation burden (TMB) and survival was also analyzed. OS was shorter for patients carrying TP53 mutation (MUT) than that of wild type (WT) (37.7m vs 52.8m; p = 0.040, HR = 1.38, 95% CI 1.01-1.89). Dual TP53/EGFR-MUT was associated with inferior OS compared with the dual WT/WT cohort (38.4m vs 51.9m; p = 0.023, HR 1.83, 95% CI 0.95-3.52). 316 DEGs between dual TP53/EGFR-MUT and dual WT/WT samples were obtained and functionalanalysismade known that DEGs were strikingly enriched in regulating the metabolism of important amino acids, cell division, cell cycle regulation, cell adhesion, and extracellular matrix composition. KEGG analysis discovered that DEGs were mainly enriched in signaling pathways such as PI3K-Akt, cytokine-cytokine receptor interaction, focal adhesions, and extracellular matrix receptor interaction.PPI network suggested that GPC3, CCL28, GPR37, and NPY genes were up-regulated in dual mutation samples. OS in the high TMB cohort was significantly better than that in the low TMB in patients with TP53 MUT(43.2m vs 32.4m; P = 0.007, HR = 0.52, 95% CI: 0.34-0.81), as well as in the combination of TP53 MUT and EGFR WT group (44.4m vs 31.2m; P = 0.021, HR = 0.55, 95% CI 0.34 - 0.89). TP53 MUT is a poor prognostic factor in LUAD patients, and the prognosis of TP53/EGFR co-mutation is worse. GPC3, CCL28, GPR37, and NPY may be novel prognostic markers and potential therapeutic targets for patients with dual TP53/EGFR mutation LUAD.

Both the presence of a micropapillary component and the micropapillary predominant subtype predict poor prognosis after lung adenocarcinoma resection: a meta-analysis

ObjectiveIt has been confirmed that the micropapillary (MP) pattern is a poor prognostic factor after resection of lung adenocarcinoma (ADC), but the proportion of the MP component as a prognostic criterion is still controversial. Hence, a meta-analysis was performed to evaluate whether the presence of an MP component has equal prognostic power as the MP predominant subtype.MethodsLiterature retrieval was performed in the MEDLINE, EMBASE, and Cochrane databases until December 23, 2019. Eligible studies were selected based on the inclusion and exclusion criteria. The included studies were divided into two subgroups, the MP component subgroup and the MP predominant subgroup, according to the proportion of the MP pattern to analyse the effect of this pattern on disease-free survival (DFS) and overall survival (OS). The hazard ratio (HR) and 95% confidence interval (CI) were extracted from each study. Review Manager 5.3 was used for statistical analyses.ResultsFinally, 10 studies, including a total of 4934 lung ADC patients, were included in this meta-analysis. Our results indicated a significantly worse pooled DFS (HR 1.62, 95% CI 1.20–2.21) and OS (HR 1.53, 95% CI 1.19–1.96) in the subgroup of MP predominant subtype patients. The pooled DFS (HR 1.80, 95% CI 1.45–2.85) and OS (HR 2.26, 95% CI 1.46–3.52) were also poor in the subgroup of patients with the presence of an MP component.ConclusionsBoth the presence of an MP component and the MP predominant subtype are related to poor DFS and OS after lung ADC resection and represent adverse prognostic factor for lung ADC patients. However, there are some limitations in this meta-analysis, and quantitative stratification based on the proportion of the MP component is needed to explore its effect on prognosis of lung ADC patients in the future.

FANCI Cooperates with IMPDH2 to Promote Lung Adenocarcinoma Tumor Growth via a MEK/ERK/MMPs Pathway.

PurposeFanconi anemia complementation group I (FANCI) is a key protein in ribosome biogenesis and DNA repair. Here, we aimed to determine the clinical significance, prognostic value and biology functions of FANCI in lung adenocarcinoma (LUAD).MethodsThe expression of FANCI in LUAD tissue and its relationship with patient outcomes were assessed using bioinformatics analysis, as well as quantitative reverse-transcription PCR (qRT-PCR) and Western blot analysis of LUAD tissue and adjacent normal lung tissue. The chi-squared test and Cox regression analysis were used to analyze the clinical significance of FANCI expression. The biological effects of FANCI knockdown in human LUAD cell lines were investigated by analysis of proliferation, colony formation, cell cycle distribution, migration, and invasion in vitro, and monitoring of tumor xenograft growth in vivo. FANCI interactions with IMPDH2 and involvement in MEK/ERK/MMPs signaling were analyzed using co-immunoprecipitation assays, immunofluorescence microscopy, and Western blotting.ResultsFANCI was identified as a hub gene for LUAD. FANCI expression was upregulated in LUAD tissues compared with normal lung tissues and was positively associated with lymphatic metastasis, distant metastasis, and poor outcome. FANCI was also an independent prognostic factor in LUAD patients. Knockdown of FANCI in LUAD cell lines decreased their proliferation, migration, invasion, and cell cycle progression in vitro, and decreased the growth of xenografts in mice. Direct binding of FANCI to IMPDH2 decreased IMPDH2 degradation, regulated activation of MEK/ERK/MMPs signaling. Overexpression of IMPDH2 reversed the inhibitory effects of FANCI knockdown.ConclusionFANCI may act as an oncogene in LUAD by cooperating with IMPDH2 to promote cell proliferation via the MEK/ERK/MMPs pathway. These results identify FANCI as a potential prognostic biomarker and therapeutic target for LUAD.

Overexpression of HSP10 correlates with HSP60 and Mcl-1 levels and predicts poor prognosis in non-small cell lung cancer patients.

BACKGROUND: HSP60 and its partner HSP10 are members of heat shock proteins (HSPs) family, which help mitochondrial protein to fold correctly. Mcl-1, a member of the Bcl-2 family, plays a crucial role in regulation of cell apoptosis. Aberrant expression of HSP10, HSP60 and Mcl-1 is involved in the development of many tumors.OBJECTIVE: To examine the association between expression of HSP10, HSP60 and Mcl-1 and clinicopathological features of non-small cell lung cancer (NSCLC).METHODS: Tissue microarrays including 53 non-cancerous lung tissues (Non-CLT) and 354 surgically resected NSCLC were stained with anti-HSP10, anti-HSP60 and anti-Mcl-1 antibodies respectively by immunohistochemistry.RESULTS: Higher expression of HSP10, HSP60 and Mcl-1 was found in NSCLC compared with Non-CLT. Both individual and combined HSP10 and HSP60 expression in patients with clinical stage III was higher than that in stage I II. Expression of HSP10 showed a positive correlation with HSP60 and Mcl-1. Overall survival time of NSCLC patients was remarkably shorter with elevated expression of HSP10, HSP60 and Mcl-1 alone and in combination. Moreover overexpression of HSP10 and Mcl-1 was poor independent prognostic factor for lung adenocarcinoma patients.CONCLUSIONS: High expression of HSP10, HSP60 and Mcl-1 might act as novel biomarker of poor prognosis for NSCLC patients.