Lung Cancer Gene Research Articles

Mutations of the Cx43 Gene in Non-Small Cell Lung Cancer: Association with Aberrant Localization of Cx43 Protein Expression and Tumor Progression

Background and Objectives: The Connexin43 (Cx43) gene is a suspected tumor suppressor gene, as re-expressed wild-type Cx43 genes reduce the malignancy potential of tumor cells. However, the role of Cx43 gene expression in human lung tumorigenesis remains unclear. Materials and Methods: Tumor tissues from 165 primary lung cancer patients were collected to study Cx43 protein expression and gene mutations using immunohistochemistry and direct DNA sequencing. In addition, Cx43 genes with or without mutations were transfected to CL-3 human lung cancer cells to confirm the function of these mutant forms of the Cx43 gene. Results: Aberrant localization of Cx43 protein in the nucleus and cytoplasm of tumor cells was detected in 14 out of 165 non-small cell lung cancer (NSCLC) patients. Mutations in the Cx43 gene were also found in patients with aberrant Cx43 localization, and transfection of these mutant genes into lung cancer cells enhanced their proliferation. Conclusions: To our knowledge, this is the first study to demonstrate Cx43 gene mutations in human lung neoplasm, supporting the hypothesis that Cx43 may function as a tumor suppressor in some lung cancer patients. Additionally, the findings suggest an association between aberrant localization of Cx43 protein expression and tumor progression.

Association of ERCC1 Gene Polymorphisms (rs3212986 and rs11615) With the Risk of Lung Cancer in a Population From Southeast Iran.

Polymorphisms within the excision repair cross-complementation group 1 (ERCC1), an essential component of DNA repair mechanisms, have been associated with various malignancies. This study aimed to evaluate the association of the single-nucleotide polymorphisms (SNPs) rs3212986 and rs11615 within the ERCC1 gene in non-small cell lung cancer (NSCLC) patients. Study Design: A case-control study. Genomic DNA was extracted from the peripheral blood samples of 83 NSCLC patients and 119 healthy individuals. The genetic diversity of SNPs rs3212986 and rs11615 was determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The RFLP results were confirmed through sequencing. The TT genotype of the rs11615 SNP was associated with a higher risk of NSCLC development (odds ratio: 3.900, 95% confidence interval: 0.603, 22.866, P=0.050). Furthermore, the AA genotype of rs3212986 was related to a higher risk of NSCLC development (OR: 2.531, 95% CI: 1.017, 6.300, P=0.046). A significant association was observed between smoking and lung cancer (OR: 3.072, 95% CI: 1.715, 5.503, P<0.001). Moreover, among non-smokers, there was an association between lung cancer risk and the AA (OR: 6.825, 95% CI: 1.722, 27.044, P=0.006) and AC (OR: 2.503, 95% CI: 0.977, 6.412, P=0.056) genotypes of rs3212986. However, no correlation was found between the genotypes of these SNPs and patients' sensitivity to cisplatin and carboplatin (P ˃ 0.05). The rs11615-related TT genotype and the rs3212986-related AA genotype may be associated with a higher risk of lung cancer development.

Identification of potential core genes in lung cancer and therapeutic traditional Chinese medicine compounds using bioinformatics analysis.

Lung cancer (LC) remains the leading cause of cancer-related death. We identified potential therapeutic targets and traditional Chinese medicine (TCM) compounds for LC treatment. GSE43346 and GSE18842 were derived from the Gene Expression Omnibus (GEO) database and used to identify differentially expressed genes (DEGs). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed using The Database for Annotation, Visualization and Integrated Discovery (DAVID). Protein-protein interactions were analyzed using STRING and Cytoscape software. Hub gene expression was validated using Gene Expression Profiling Interactive Analysis and the Human Protein Atlas. Kaplan-Meier survival analysis was conducted to evaluate the prognostic value of hub genes in patients with LC. Therapeutic TCM compounds were screened using the Comparative Toxicogenomics Database, and DEGs were largely enriched in biological processes, including cell division and mitotic nuclear division, such as the cell cycle and p53 signaling pathways. Elevated expression of hub genes was observed in LC samples. Overexpression of CDC20, CCNB2, and TOP2A is an unfavorable prognostic factor for postprogressive survival in patients with LC. Paclitaxel, quercetin, and rotenone have been identified as active substances in TCM. CDC20, CCNB2, and TOP2A are novel hub genes associated with LC. Paclitaxel, quercetin, and rotenone can be used as therapeutic agents in TCM.

Cascade amplification-based triple probe biosensor for high-precision DNA hybridization detection of lung cancer gene

As an essential biomarker for diagnosing and treating various diseases, low-cost, quantitative detection methods for complementary DNA (cDNA) have received much attention. The surface plasmon resonance (SPR) sensing technique is an effective measurement scheme, but the ambient temperature and pH variations have a non-negligible impact. In this work, we developed a triple-probe SPR sensing system for detecting cDNA concentration, temperature, and pH. In order to satisfy the triple parameter measurements, we used a microstructured optical fiber as the sensing platform, silver and gold films as the excitation layer, and a MoS2 film as the modulation layer. First, we explore the modulation mechanism of SPR and the conditions for excitation of triple SPR and demonstrate that the carrier concentration is a crucial factor affecting the resonance wavelength. Then, the feasibility of the sensing system for triple-probing is theoretically analyzed. Finally, in the experiment, the optimal parameters of the sensor were determined, and the triple parameter detection was successfully realized. The experimental results show that the three probes can work independently, and the hybridized DNA probe can realize the selective detection of cDNA with a sensitivity of 0.249 nm/(nmol/l). The maximum sensitivity of the pH probe and the temperature probe are 51.5 nm/pH and 6.14 nm/°C. In addition, the experimental results show that the sensing probes have excellent reproducibility. This paper’s innovation is using the fiber optic SPR effect to achieve quantitative detection for cDNA, temperature detection, and pH detection. Therefore, the sensor has a promising future in early diagnosis and biosensing.

Differentially Expressed Genes in Lung Cancer: Molecular Docking of Hypoxanthine Guanine-Phosphoribosyl Transferase with Dibutyl Phthalate

Differentially Expressed Genes in Lung Cancer: Molecular Docking of Hypoxanthine Guanine-Phosphoribosyl Transferase with Dibutyl Phthalate

The clinical significance of endoplasmic reticulum stress related genes in non-small cell lung cancer and analysis of single nucleotide polymorphism for CAV1.

In recent years, protein homeostasis imbalance caused by endoplasmic reticulum stress has become a major hallmark of cancer. Studies have shown that endoplasmic reticulum stress is closely related to the occurrence, development, and drug resistance of non-small cell lung cancer, however, the role of various endoplasmic reticulum stress-related genes in non-small cell lung cancer is still unclear. In this study, we established an endoplasmic reticulum stress scores based on the Cancer Genome Atlas for non-small cell lung cancer to reflect patient features and predict prognosis. Survival analysis showed significant differences in overall survival among non-small cell lung cancer patients with different endoplasmic reticulum stress scores. In addition, endoplasmic reticulum stress scores was significantly correlated with the clinical features of non-small cell lung cancer patients, and can be served as an independent prognostic indicator. A nomogram based on endoplasmic reticulum stress scores indicated a certain clinical net benefit, while ssGSEA analysis demonstrated that there was a certain immunosuppressive microenvironment in high endoplasmic reticulum stress scores. Gene Set Enrichment Analysis showed that scores was associated with cancer pathways and metabolism. Finally, weighted gene co-expression network analysis displayed that CAV1 was closely related to the occurrence of non-small cell lung cancer. Therefore, in order to further analyze the role of this gene, Chinese non-smoking females were selected as the research subjects to investigate the relationship between CAV1 rs3779514 and susceptibility and prognosis of non-small cell lung cancer. The results showed that the mutation of rs3779514 significantly reduced the risk of non-small cell lung cancer in Chinese non-smoking females, but no prognostic effect was found. In summary, we proposed an endoplasmic reticulum stress scores, which was an independent prognostic factor and indicated immune characteristics in the microenvironment of non-small cell lung cancer. We also validated the relationship between single nucleotide polymorphism locus of core genes and susceptibility to non-small cell lung cancer.

Beyond tobacco: genomic disparities in lung cancer between smokers and never-smokers

BackgroundTobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10–20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile.MethodsWe conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment.ResultsOur findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1.ConclusionsWe found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.

Non-small Cell Lung Cancer with Metachronous Mutations of EGFR and ALK Genes: A Case Report and Literature Review

Multiple primary lung cancer (MPLC) refers to patients with two or more primary lesions of lung cancer. It can be divided into synchronous MPLC (sMPLC) and metachronous MPLC (mMPLC) based on the timing of occurrence. In recent years, the detection rate of MPLC has gradually increased. However, considerable controversy exists in distinguishing MPLC from intrapulmonary metastasis (IM), especially when the histopathological types are identical. Given the significant differences in treatment strategies and prognosis in clinical practice currently, accurate diagnosis of MPLC is crucial for personalized precision therapy. Molecular genetics and sequencing technologies offer effective strategies for assessing the clonal origin of tumors. There have been reports of coexisting mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) fusion genes in non-small cell lung cancer, but case of EGFR mutation following an ALK mutation has not been mentioned. This article accurately diagnoses and retrospectively analyzes the clinical data of a case of ALK mutant adenocarcinoma in a male patient who developed an EGFR mutation with multiple metastases four years after surgery, and reviews the relevant literature. This paper aims to deepen the understanding of mMPLC and provide clinical references for the diagnosis and treatment of such patients. .

Next-generation sequencing as a valuable tool for mutational spectrum in advanced-stage NSCLC patients.

Lung cancer remains one of the most threatening malignancies, ranking as the second most diagnosed cancer, and it continues to be the leading cause of cancer-related deaths worldwide. Challenges persist with late diagnosis and the high mutational burden characteristic of lung cancer. Our study focuses on identifying the mutational spectrum of a cohort of advanced-stage non-small cell lung cancer (NSCLC) patients using a minimally invasive method through blood collection. To analyze the mutational landscape of these patients, we employed plasma DNA for the next-generation sequencing (NGS) cancer panel Ion Torrent, which contains 50 of the most mutated genes in lung cancer. All protocols for extraction, quality and quantity control, and library preparation follow the manufacturer's rules. Bioinformatics analysis was performed to select pathogenic mutations versus non-pathogenic-benign ones. This approach is particularly valuable for patients in advanced stages (III and IV, n=10) of lung adenocarcinoma and lung squamous cell carcinoma, who lack surgical options and limited therapeutic avenues. The comprehensive sequencing analysis revealed that nine of the ten lung cancer patients carried a TP53 mutation. Also, several other mutations exist in various cases, showing heterogeneous profiling. Our findings demonstrate the potential of liquid biopsies in providing crucial genetic insights that can guide personalized treatment strategies, improving the management and outcomes for patients with advanced lung cancer.

Network Pharmacological Study of the Active Ingredient of Panax Notoginseng Saponins for the Treatment of Lung Cancer by Inhibiting AKR1C3

Background: Lung cancer is the malignancy with the second highest diagnostic rate and the leading cause of cancer-related death. Objective: This study aims to investigate the potential mechanism and molecular targets of Panax notoginseng saponins (PNS) in inhibiting lung cancer through network pharmacology. Methods: Pharmacodynamic targets of each compound of PNS were searched from TargetNet, SwissTargetPrediction, and BatMan-TCM databases. Next, the differential expression genes (DEGs) in lung cancer were obtained from the Gene Expression Omnibus (GEO) database and screened by R package. Later, the STRING 11.0 database was utilized to analyze the protein-protein interaction (PPI) network of common targets of PNS-lung cancer, clusterProfiler to perform gene ontology (GO) annotation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for the common targets, and Cytoscape 3.8.0 to construct and analyze the "ingredient-target" network for the common targets of PNS-lung cancer. Results: A total of 154 potential pharmacodynamic targets of PNS, 2399 DEGs of lung cancer-related diseases, and 21 common targets of PNS-lung cancer were obtained by database search and screening. The 21 common targets were mainly involved in biological processes (such as small molecule metabolism and cytokine production) and were major components of cellular structures (such as neuronal cell bodies and membrane rafts). Besides, these targets could function as carboxylic ester hydrolases, G protein-coupled amine receptors, and oxidoreductase. They were mainly enriched in 14 signaling pathways, like neuroactive ligand-receptor interaction, regulation of lipolysis in adipocytes, and calcium signaling pathway. Furthermore, the molecular docking results revealed that aldo-keto reductase family 1 member C3 (AKR1C3) and melanin metabolic enzyme (MME) may be direct targets of ginsenoside Rg1 and notoginsenoside R2. Conclusion: Our study showed that ginsenosides inhibit the progression of lung cancer through multiple targets and pathways. More importantly, PNS may treat lung cancer by directly inhibiting AKR1C3.

The clinical features and prognostic implications of the co-mutated TP53 gene in advanced non-small cell lung cancer.

TP53 is a frequently mutated oncogene within non-small cell lung cancer (NSCLC). However, the clinical and prognostic significance of co-mutations in TP53 in patients with advanced NSCLC has not been fully elucidated. A total of 174 patients with advanced NSCLC were enrolled in this study. All patients were subjected to sequencing analysis of tumor-related genes and information such as PD-L1 expression, TMB, and co-mutation changes were collected. Patients were categorized into TP53 mutant and TP53 wild-type groups according to their TP53 mutation status and then statistically analyzed. TP53 mutations were the most common among all patients, accounting for 56.32%, followed by epidermal growth factor receptor mutations at 48.27%. The most common mutation sites in the TP53 mutation group were exons 5-8.TP53 mutations were significantly associated with PD-L1 and TMB levels. Univariate Cox analysis showed that gender and EGFR mutation affected the prognosis of TP53-mutated NSCLC patients, and multivariate Cox regression analysis identified EGFR mutation as an independent risk factor. The OS of NSCLC patients in the TP53 mutation group was significantly shorter than that of the TP53wt group. Survival curves in the TP53/EGFR combined mutation group showed that patients with combined EGFR mutation had a lower survival rate. TP53 mutations are associated with different clinical indicators and have important implications in clinical treatment. TP53 is a poor prognostic factor for NSCLC patients, and TP53/EGFR co-mutation will affect the survival time of patients. TP53/EGFR co-mutation may be a new prognostic marker for NSCLC.

Abstract PR004: Computational discovery of paralog dependencies drives target identification in lung cancer

Abstract Lung cancer is the leading cause of cancer-related death in the United States, and worldwide, with the 5-year survival rate of non-small cell lung cancer at 24%. Treatment options are limited, and even in cancers that harbor druggable biomarkers, resistance is near-universal. Identifying novel treatment strategies is essential to improve the outcomes of patients with lung cancer and provide secondary strategies for those who acquire resistance to first-line therapeutics. Identifying targeted therapies based on the genotype or expression pattern of cancers is an ongoing endeavor, and has been fruitful in the discovery of identifying cancer vulnerabilities. In lung cancer, treatment of patients that harbor activating mutations in EGFR with specific EGFR inhibitors has improved progression-free survival rates and extended the lifespan of patients diagnosed with this aggressive cancer, demonstrating the utility of targeted therapies based genetic-based vulnerabilities, or synthetic lethal interactions. A rich source of synthetic lethal genetic interactions are paralogous genes. Paralogs result from gene duplication events through evolutionary history, and many paralogs share both sequence homology and functional redundancy. Co-targeting of some paralogous genes induces a fitness defect that is synergistic compared to individual paralog loss alone. Nearly 70% of genes in the human genome are considered paralogs, and until recent efforts from the Berger lab and others, this buffering effect has caused them to be under-represented in lethality studies. Identifying frequently-inactivated paralog genes in lung cancer will provide a platform to identify new vulnerabilities in lung cancer and other cancer types that share mutational backgrounds. To identify patterns of mutation and expression of paralog genes in lung cancer, we have accessed publicly available data sets for both cell line and patient tumor samples. Using TCGA and CCLE data sources, and a set of 1030 paralog pairs identified previously by the Berger lab as potential drug targets, we have identified paralog genes that harbor high mutational frequencies in lung cancer. Using these early candidates, we next asked whether genetic inactivation or transcriptional repression of one paralog influences the essentiality of its paired gene using CERES scores generated by the Cancer Dependency Map. Preliminary results from this work has identified several paralog pairs with distinct dependency profiles in cell lines for which expression of one paralog is lost, including paralog pairs MAGOH/MAGOHB and TLK1/TLK2. Further work to characterize these dependencies in relevant cell line models is ongoing. Additionally, the druggability of these targets will be tested using targeted degradation using the dTAG system. This work will uncover a new set of paralog synthetic lethality targets, and further validate the utility of targeting known synthetic lethal paralogs for the treatment of highly lethal lung cancer. Citation Format: Alice H. Berger, Siobhan O'Brien. Computational discovery of paralog dependencies drives target identification in lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr PR004.

Oncolytic adenovirus encoding LHPP exerts potent antitumor effect in lung cancer

LHPP has been shown to be a new tumor suppressor, and has a tendency to be under-expressed in a variety of cancers. Oncolytic virotheray is a promising therapeutics for lung cancer in recent decade years. Here we successfully constructed a new recombinant oncolytic adenovirus GD55-LHPP and investigated the effect of GD55-LHPP on the growth of lung cancer cells in vitro and in vivo. The results showed that LHPP had lower expression in either lung cancer cells or clinical lung cancer tissues compared with normal cells or tissues, and GD55-LHPP effectively mediated LHPP expression in lung cancer cells. GD55-LHPP could effectively inhibit the proliferation of lung cancer cell lines and rarely affected normal cell growth. Mechanically, the oncolytic adenovirus GD55-LHPP was able to induce stronger apoptosis of lung cancer cells compared with GD55 through the activation of caspase signal pathway. Notably, GD55-LHPP also activated autophagy-related signal pathway. Further, GD55-LHPP efficiently inhibited tumor growth in lung cancer xenograft in mice and prolonged animal survival rate compared with the control GD55 or PBS. In conclusion, the novel construct GD55-LHPP provides a valuable strategy for lung cancer-targeted therapy and develop the role of tumor suppress gene LHPP in lung cancer gene therapy.

Novel Transcriptional and DNA Methylation Abnormalities of SORT1 Gene in Non-Small Cell Lung Cancer.

Sortilin is an important regulator with potential tumour-suppressor function by limiting EGFR signalling. In this study, we undertook a comprehensive expression analysis of sortilin transcript variants and the DNA methylation status of their corresponding promoters in human non-small cell carcinomas (NSCLCs). RNA/DNA was extracted from 81 NSCLC samples and paired normal tissue. mRNA expression was measured by qPCR and DNA methylation determined by pyrosequencing. BigDye-terminator sequencing was used to confirm exon-8 alternative splicing. Results demonstrated that both SORT1A and SORT1B variants were downregulated in lung tumours. The SORT1A/SORT1B expression ratio was higher in tumours compared to normal tissue. SORT1B promoter hypermethylation was detected in lung tumours compared to normal lung (median difference 14%, Mann-Whitney test p = 10-6). Interestingly, SORT1B is hypermethylated in white blood cells, but a small and very consistent drop in methylation (6%, p = 10-15) was observed in the lung cancer cases compared to control subjects. We demonstrate that the SORT1B exon-8 splice variation, reported in sequence databases, is also a feature of SORT1A. The significantly altered quantitative and qualitative characteristics of sortilin mRNA in NSCLC indicate a significant involvement in tumour pathogenesis and may have significant impact for its utility as a predictive marker in lung cancer management.

A retrospective study of first-line therapy and subsequent pyrotinib treatment in advanced lung adenocarcinoma with HER2 mutations.

HER2 is an infrequently mutated driver gene in non-small cell lung cancer (NSCLC). At present, there has been no comprehensive large-scale clinical study to establish the optimal first-line treatment strategy for advanced lung adenocarcinoma (LUAD) with HER2-Mutant. Besides that, the effectiveness and safety of pyrotinib, a pan-HER inhibitor, in the context of NSCLC are still undergoing investigation. In this study, we conducted a retrospective data collection of HER2-Mutated advanced LUAD who received first-line treatment and pyrotinib between May 2014 and June 2023. Patients treated with chemotherapy, chemotherapy + immune checkpoint inhibitors (ICIs), chemotherapy + bevacizumab and pyrotinib in first-line treatment. Furthermore, we collected data on the efficacy and safety of pyrotinib in these patients after disease progression. The main endpoint of the study was progression-free survival (PFS). In the final analysis, 89 patients were included in the first-line cohort and 30 patients were included in the pyrotinib cohort. In the first-line treatment cohort, chemotherapy + ICIs, chemotherapy + bevacizumab, and pyrotinib exhibited notable survival benefits compared to chemotherapy (median PFS: 9.87 vs. 7.77 vs. 7.10 vs. 5.40 months, p-value < 0.05). Furthermore, patients with a first-line treatment PFS of less than 6 months may potentially benefit from subsequent treatment with pyrotinib (median PFS: 7.467 vs. 3.000, p-value = 0.0490). In the first-line treatment of HER2-Mutant LUAD, regimens involving combinations like chemotherapy + ICIs, chemotherapy + bevacizumab, and pyrotinib may confer enhanced survival advantages compared to chemotherapy. Nevertheless, no significant distinctions were observed among these three treatment strategies, underscoring the imperative to identify biomarkers for the discerning selection of suitable therapeutic modalities. Moreover, patients with suboptimal response to first-line treatment may potentially derive more benefit from pyrotinib.

Malignant effusion aspirate for use in constructing organoids model to assist individualized treatment of advanced non-small cell lung cancer.

e20526 Background: Organoids derived from cancer patients are considered to represent the overall appearance of the original tumor in lung cancer. With the in-depth study of molecular mechanisms and the development of new drugs, the survival time of advanced non-small cell lung cancer has been greatly extended. However, when it comes to the back-end treatment, they often have limited amounts of fresh tissue samples or cannot complete puncture, which affects the successfully establishment of organoids. Some patients often have malignant pleural effusion (MPE) requiring repeated aspiration, so it is clinically easy to obtain. Our goal was to culture organoids from malignant effusion of advanced NSCLC patients (LCO), and explore and analyze the consistency of drug sensitivity with clinical practice. Methods: In this study, malignant pleural effusion specimens of 39 patients with NSCLC were collected and complete clinical information was obtained.The partially paired successfully modeled organoids and the original malignant effusion were sequenced by WES(N = 7) and RNA(N = 6) for genetic background consistency.All successfully cultured organoids were subjected to drug sensitivity test, and the drug sensitivity results were compared with the actual therapeutic effect of clinical patients. Results: We successfully established 34 LCOs with a success rate of 87.2% . LCOs retained the mutation spectrum of the matching primary tumor. TP53 and EGFR were the most frequently mutated genes, occurring in 83.3% (5 of 6) and 66.7% (4 of 6) of effusion samples. On average, LCOs retained an 93.2% overlap of the most frequently lung cancer gene mutational variants from the parental MPE samples.The gene expression in the paired LCOs and effusion samples were compared, demonstrating an average 80% overlap in gene expression between the LCOs and the matching effusion samples.The clinical outcomes of the 25 patients (27 rounds of treatment) and their LCOs pharmaco-phenotyping results are analyzed. Notably, 94.7% of the treatments, which include at least one drug that was tested to be sensitive or moderately responsive by LCOs, achieved partial response or stable disease. However, 62.5% of the treatments, which do not include any drug that was tested to be sensitive or moderately responsive by LCOs, developed progressive disease. Overall, the LCO pharmaco-phenotyping results are highly correlated with clinical outcomes, with 85.2% accuracy (95% CI, 67.5–94.1%), 85.7% sensitivity (95% CI, 62.6–96.2%), and 83.3% specificity (95% CI, 36.5–99.1%). Conclusions: The effusion and LCOs have high concordance of genomic profiling. Organoid culture from malignant effusions of lung cancer can be used as a platform for drug sensitivity testing. These LCOs may be helpful in individualized treatment of NSCLC.

Deciphering the Role of miR-30a-5p and DLGAP1 Gene in Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the deadliest form of cancer worldwide. Understanding the mechanisms of lung cancer development is vital for targeted therapy advancements. This article explores the little-known role of the guanylate kinase-associated protein (GKAP), encoded by the Disks large-associated protein 1 (DLGAP1) gene, in NSCLC along with assessing microRNA-30a-5p's influence on DLGAP1 gene expression in the A549 cell line. Experiments were conducted on A549 cells transfected with synthetic oligonucleotides. The luciferase assay was employed to confirm the binding site of miR-30a-5p to the 3'UTR of DLGAP1 mRNA. The role of miRNA-30a-5p mimic in regulating potential target gene expression at the protein and mRNA levels was studied by performing RT-qPCR and western blot analyses. The effects of DLGAP1 knockdown and miRNA-30a-5p mimic on cell viability and the cell cycle were evaluated using the MTT test and flow cytometry with annexin/iodide cell staining. The luciferase assay indicated that miR-30a-5p has the ability to bind to the 3'UTR of DLGAP1 mRNA. RT-qPCR revealed that the overexpression of miR-30a-5p down-regulates DLGAP1 mRNA. Western blot analysis indicated that miR-30a-5p slightly reduces the level of the GKAP protein. Knockdown of DLGAP1 with synthetic oligonucleotides, as well as transfection with a miR-30a-5p mimic, significantly attenuates cell proliferation and increases the number of cells in the early and late stages of apoptosis. Our findings reveal the antiproliferative effect of miR-30a-5p and DLGAP1 gene knockdown on A549 cancer cells, implying that these elements could be considered as therapeutic targets for personalized medicine in NSCLC patients.

Revealing prognostic insights of programmed cell death (PCD)-associated genes in advanced non-small cell lung cancer.

The management of patients with advanced non-small cell lung cancer (NSCLC) presents significant challenges due to cancer cells' intricate and heterogeneous nature. Programmed cell death (PCD) pathways are crucial in diverse biological processes. Nevertheless, the prognostic significance of cell death in NSCLC remains incompletely understood. Our study aims to investigate the prognostic importance of PCD genes and their ability to precisely stratify and evaluate the survival outcomes of patients with advanced NSCLC. We employed Weighted Gene Co-expression Network Analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO), univariate and multivariate Cox regression analyses for prognostic gene screening. Ultimately, we identified seven PCD-related genes to establish the PCD-related risk score for the advanced NSCLC model (PRAN), effectively stratifying overall survival (OS) in patients with advanced NSCLC. Multivariate Cox regression analysis revealed that the PRAN was the independent prognostic factor than clinical baseline factors. It was positively related to specific metabolic pathways, including hexosamine biosynthesis pathways, which play crucial roles in reprogramming cancer cell metabolism. Furthermore, drug prediction for different PRAN risk groups identified several sensitive drugs explicitly targeting the cell death pathway. Molecular docking analysis suggested the potential therapeutic efficacy of navitoclax in NSCLC, as it demonstrated strong binding with the amino acid residues of C-C motif chemokine ligand 14 (CCL14), carboxypeptidase A3 (CPA3), and C-X3-C motif chemokine receptor 1 (CX3CR1) proteins. The PRAN provides a robust personalized treatment and survival assessment tool in advanced NSCLC patients. Furthermore, identifying sensitive drugs for distinct PRAN risk groups holds promise for advancing targeted therapies in NSCLC.

Advances of Molecular Targeted Therapy in EGFR-mutated Squamous Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is a prevalent tumour type in our country, with lung squamous carcinoma being a commonly observed NSCLC subtype besides lung adenocarcinoma. Epidermal growth factor receptor (EGFR) is a significant driver gene in lung cancer, and EGFR mutation frequency is considerably lower in lung squamous carcinoma in comparison to lung adenocarcinoma. Although targeted therapy against EGFR has demonstrated significant advancements in lung adenocarcinoma, while progress in lung squamous carcinoma has been relatively sluggish. This paper reviews recent studies on molecular targeted therapy for EGFR-mutated lung squamous carcinoma and summarises the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in treating squamous carcinoma of the lung, in order to provide a reference for treating patients with EGFR-mutated squamous carcinoma of the lung. .

PheSeq, a Bayesian deep learning model to enhance and interpret the gene-disease association studies

Despite the abundance of genotype-phenotype association studies, the resulting association outcomes often lack robustness and interpretations. To address these challenges, we introduce PheSeq, a Bayesian deep learning model that enhances and interprets association studies through the integration and perception of phenotype descriptions. By implementing the PheSeq model in three case studies on Alzheimer’s disease, breast cancer, and lung cancer, we identify 1024 priority genes for Alzheimer’s disease and 818 and 566 genes for breast cancer and lung cancer, respectively. Benefiting from data fusion, these findings represent moderate positive rates, high recall rates, and interpretation in gene-disease association studies.