Lung Cancer Gene Research Articles

Equivocating and Deliberating on the Probability of COVID-19 Infection Serving as a Risk Factor for Lung Cancer and Common Molecular Pathways Serving as a Link

The COVID-19 infection caused by SARS-CoV-2 in late 2019 posed unprecedented global health challenges of massive proportions. The persistent effects of COVID-19 have become a subject of significant concern amongst the medical and scientific community. This article aims to explore the probability of a link between the COVID-19 infection and the risk of lung cancer development. First, this article reports that SARS-CoV-2 induces severe inflammatory response and cellular stress, potentially leading to tumorigenesis through common pathways between SARS-CoV-2 infection and cancer. These pathways include the JAK/STAT3 pathway which is activated after the initiation of cytokine storm following SARS-CoV-2 infection. This pathway is involved in cellular proliferation, differentiation, and immune homeostasis. The JAK/STAT3 pathway is also hyperactivated in lung cancer which serves as a link thereof. It predisposes patients to lung cancer through myriad molecular mechanisms such as DNA damage, genomic instability, and cell cycle dysregulation. Another probable pathway to tumorigenesis is based on the possibility of an oncogenic nature of SARS-CoV-2 through hijacking the p53 protein, leading to cell oxidative stress and interfering with the DNA repair mechanisms. Finally, this article highlights the overexpression of the SLC22A18 gene in lung cancer. This gene can be overexpressed by the ZEB1 transcription factor, which was found to be highly expressed during COVID-19 infection.

Unveiling Immunotherapy Evasion in Lung Cancer: The Role of Fanconi Anemia and Stemness Genes in Shaping an Immunosuppressive Microenvironment.

The study aimed to investigate the fanconi anemia (FA)-related and stemness-related genes in lung cancer (LC) patients. Firstly, we identified stemness-related genes through weighted gene co-expression network analysis combined with TCGA database. Further combined stemness-related genes with FA-related genes to screen for prognostic-related genes. Risk score was constructed from the screened genes and comprehensive bioinformatics analyses were performed. Finally, single-cell data and in vitro experiment were used to validate our results. We screened a total of eight genes to construct a risk score. The risk score was an independent prognostic factor for LC. The validation results of multiple GEO databases were consistent with our results. Functional and pathway enrichment analysis showed that risk score was associated with cell cycle, DNA replication, DNA damage repair, and immune-related pathways. The results showed to be related to the stem cell self-renewal and proliferation. Besides, we also found that patients with higher risk scores had lower immune activity and function, and the effectiveness of immunotherapy might be poorer, with a higher rate of immune escape. Finally, our results revealed that SLC2A1 had the highest correlation with B cells in single-cell data analysis, and we validated its correlation with B cells and its expression with FA-related genes, tumor invasiveness, stemness, and drug sensitivity. Our research constructed a risk score based on FA-related and tumor stemness-related specific genes. In addition to accurately predicting the prognosis of patients with LC, the risk score may also serve as an innovative and viable predictor of immunotherapy response.

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.

Identification of Cancer Stem Cell (CSC)-Associated Genes, Prognostic Value, and Candidate Drugs as Modulators of CSC-Associated Signaling in Carcinomas Through a Multiomics Data Analysis Approach

Background: Cancer stem cells (CSCs) are a small subpopulation of cancer cells that have the potential for self-renewal and a strong proliferative capacity, and sustain tumorigenesis capabilities. This ability of CSCs to escape immune responses makes the CSCs a primary source of functionally altered, immune-resistant, chemoresistant, aggressive tumor cells. These characteristics determine the potential advantage of targeting CSCs for the treatment of solid tumors. Method: First, we downloaded different gene expression datasets of CSCs from the NCBI-GEO (National Center for Biotechnology Information–Gene Expression Omnibus) database and identified common genes by using a suitable Venn tool. Subsequently, we explored the prognostic significance of the particular genes in particular cancers and analyzed the expression of these genes at the protein level in human solid tumors by using KM plotter (Kaplan-Meier plotter) and an HPA (The Human Protein Atlas) database, respectively. Finally, using a comparative toxicogenomic database, we selected several important drugs or chemicals. Result: From this study, we identified APOC1 as a common upregulated gene in breast cancer and SLC44A5 and CAV2 as common up- and downregulated genes in lung cancer. In ovarian cancer, PRRG4 is a commonly upregulated gene, and ADCY7, AKAP12, TPM2, and FLNC are commonly downregulated genes. These genes also show prognostic significance in respective cancers. Several drugs that are capable of targeting the expression or signaling network of designated genes of CSC were also identified, which may contribute in CSC-targeted cancer therapy. Conclusion: Our study suggests a need for more in-depth experimental investigations to determine the actual functional activity and the mechanism of action of these CSC-associated genes.

Unveiling the impact of C15orf48 on non-small cell lung cancer through NF-kappa B signaling.

The role of the C15orf48 gene in lung cancer is not well understood. This study aimed to investigate the effect of C15orf48 in non-small cell lung cancer (NSCLC). Bioinformatics analyses were performed using Oncomine, The Cancer Genome Atlas (TCGA), Protein-Protein Interaction (PPI) networks, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Immunohistochemical staining was used to detect C15orf48 expression in tissue microarrays. Cellular assays, including CCK8, colony formation, wound healing, transwell migration, flow cytometry, and cell adhesion, were conducted to assess cell viability, proliferation, invasion, and apoptosis. A xenograft tumor model was used to examine tumor growth, and Western blotting was used to detect protein expression. C15orf48 expression was significantly upregulated in tumor tissues compared to normal tissues and was associated with poor prognosis. Knockdown of C15orf48 in A549 and H1299 cells reduced proliferation, invasion, and adhesion while increasing apoptosis. C15orf48 knockdown also inhibited tumor growth in vivo and was associated with immune cell infiltration. Although C15orf48 expression correlated with the epithelial-mesenchymal transition (EMT) score, no significant differences were observed. GSEA identified the NF-κB signaling pathway as a key pathway involved. Proteins PLAUR, IKBα, IL-1RN, ICAM1, and TMPRSS4 showed decreased expression in the shC15orf48 group compared to the shCtrl group. We concluded that C15orf48 promotes NSCLC progression, potentially through immune cell infiltration and the NF-κB signaling pathway.

Breathing new insights into the role of mutant p53 in lung cancer.

The tumour suppressor gene p53 is one of the most frequently mutated genes in lung cancer and these defects are associated with poor prognosis, albeit some debate exists in the lung cancer field. Despite extensive research, the exact mechanisms by which mutant p53 proteins promote the development and sustained expansion of cancer remain unclear. This review will discuss the cellular responses controlled by p53 that contribute to tumour suppression, p53 mutant lung cancer mouse models and characterisation of p53 mutant lung cancer. Furthermore, we discuss potential approaches of targeting mutant p53 for the treatment of lung cancer.

Divergent clinical and immunologic outcomes based on STK11 co-mutation status in resectable KRAS-mutant lung cancers following neoadjuvant immune checkpoint blockade.

Co-mutations of the KRAS and STK11 genes in advanced non-small cell lung cancer (NSCLC) are associated with immune checkpoint blockade (ICB) resistance. While neoadjuvant chemoimmunotherapy is now a standard of care treatment for resectable NSCLC, the clinical and immunologic impact of KRAS andSTK11 co-mutations in this setting are unknown. We evaluated and compared recurrence-free survival of resectable KRAS-mutated NSCLC tumors, with or without co-occuring STK11 mutations, treated with neoadjuvant ICB. Single cell transcriptomics was performed on tumor-infiltrating T cells from 7 KRASmut/STK11wttumors and 6 KRASmut/STK11mut tumors. Relative to KRASmut/STK11wttumors, KRASmut/STK11mut exhibited significantly higher recurrence risk. Single-cell transcriptomics showed enhanced oxidative phosphorylation with evidence of decreased PGE-2 signaling and increased IL-2 signaling in CD8+ tumor-infiltrating lymphocytes (TIL) from KRASmut/STK11mut tumors, a finding that was mirrored in KRASwt tumors that relapsed. TIL from KRASmut/STK11mut tumors expressed high levels of molecules associated with tumor residence, including CD39 and ZNF683 (HOBIT). These divergent T cell transcriptional fates suggest T cell maintenance and residence may be detrimental to anti-tumor immunity in the context of neoadjuvant ICB for resectable NSCLC, regardless of KRAS mutation status. Our work provides a basis for future investigations into the mechanisms underpinning PGE-2 and IL-2 signaling as they relate to T cell immunity to cancer and to divergent clinical outcomes in KRASmut/STK11mut NSCLC treated with neoadjuvant ICB.

Overview of Systematic Reviews of ICIs in NSCLC With EGFR, ALK, ROS1, and RET Actionable Driver Mutations

The effectiveness and safety of immune checkpoint inhibitor (ICI) monotherapy in patients with previously treated advanced or metastatic non–small cell lung cancer with EGFR, ALK, ROS1, or RET actionable driver mutations or chromosomal rearrangements is currently uncertain. We assessed the efficacy and safety of ICIs in patients with this condition whose disease did not respond well to previous chemotherapy. We reviewed 13 systematic reviews of randomized controlled trials (RCTs). The quality assessment of these reviews revealed critical methodological flaws. All 13 systematic reviews focused on survival and progression-free survival (PFS) for patients with non–small cell lung cancer and EGFR gene mutations. The systematic reviews generally considered the same set of 4 clinical trials and did not report on other outcomes or patient groups, except for 1 review that looked at patients with different levels of anti-PD-L1 expression. We found no evidence on the efficacy and safety of ICIs in patients with ALK, ROS1, or RET mutations. Overall, the systematic reviews concluded that using ICIs alone, as a second-line therapy or beyond, does not significantly improve overall survival (OS) and PFS compared to chemotherapy in patients with non–small cell lung cancer with EGFR gene mutations. No conclusions can be made regarding the benefits of ICIs in patients with EGFR mutations based on histology or high antiprogrammed death-ligand 1 antibody expression levels. The safety of ICIs in patients with EGFR, ALK, ROS1, or RET actionable driver mutations could not be assessed because of the lack of evidence provided in the included systematic reviews.

Revealing 5-(3,5-difluorobenzyl)-1H-indazole as the active pharmacophore of ALK/ROS1 dual inhibitors through theoretical calculations and biological activity evaluations

Anaplastic lymphoma kinase (ALK) and tyrosine protein kinase (ROS1) are recognized as driver genes in lung cancer, with dual inhibition of both targets offering a promising approach to enhance therapeutic outcomes in non-small cell lung cancer (NSCLC). Although numerous ALK/ROS1 inhibitors have received FDA approval, detailed research into the essential active structural motifs within these inhibitors remains limited. Addressing this gap, the current study employed computer-aided drug design (CADD) methodologies, incorporating bioisosteric and conformational similarity principles to design and synthesize 31 dual-target 2-morpholinobenzamide derivatives. These derivatives each include the 5-(3,5-difluorobenzyl)-1H-indazole, 4-benzylmorpholine, and thiophene moieties. Based on docking binding energies, we proposed that 5-(3,5-difluorobenzyl)-1H-indazole may represent a key pharmacophore for ALK/ROS1 activity. Subsequent kinase and cellular assays validated this hypothesis, with compound X4 exhibiting optimal inhibitory activity against both ALK and ROS1 kinases and lung cancer cell lines, achieving IC50 values of 0.512 µM (ALK), 0.766 µM (ROS1), and 0.034 ± 0.002 µM (H2228). In vitro antitumor assays demonstrated dose-dependent induction of apoptosis in H2228 cells by X4. Western blot (WB) analysis further confirmed that X4 effectively suppresses the expression of p-ALK and p-ERK. Importantly, X4 exhibited high specificity in targeting ALK and ROS1 across a range of kinases. In an H2228 xenograft model, X4 achieved a tumor inhibition rate of 54.71 %, underscoring its considerable potential in ALK/ROS1 inhibition.

A Prospective Observational Study on Analyzing Lung Cancer Gene Mutation Variant Allele Frequency (VAF) and Its Correlation with Treatment Efficacy.

A few studies have reported on the variability of the variant allele frequency (VAF) of gene mutations and the relationship between VAF and the therapeutic effect of molecular-targeted drugs. This joint study was conducted from May 2020 to January 2022 between St. Marianna University School of Medicine and the DNA Chip Research Institute. Cytology samples were used to verify the usefulness of a lung cancer compact panel test, which is a high-sensitivity next-generation sequencing (NGS) gene panel test. We analyzed the distribution of VAF and the duration of the initial molecular-targeted drug administration in patients with advanced-stage epidermal growth factor receptor (EGFR) mutations. Of the 196 patients diagnosed with non-small cell carcinoma (NSCLC), gene mutations were detected in 114 (58.2%) cases and in 68.7% of patients with adenocarcinomas (an increased detection rate). A VAF of 30% or more for DNA mutations was confirmed in 35 patients (33.7%), 10% to <30% in 38 (36.5%), and <10% in 31 (29.8%), including 18 patients (17.3%) with <6%, which is considered the lower limit of the LOD for other companion diagnostic kits. EGFR mutations were detected in 59 patients (30%), of whom 35 were in an advanced stage and received molecular-targeted drugs as their initial treatment. Groups A and B comprised patients with a VAF of ≥10% and <10%, respectively, with 27 patients (median VAF 30.6%, range 11.4-77%) in group A and 8 (median VAF 5.4%, range 0.1-8.5%) in group B. The duration of the administration of molecular-targeted drugs was 17 months (range 3-42 months) in group A and 14 months (range 1-45 months) in group B, with no statistically significant difference between the two groups (p-value = 0.7). Twenty-seven percent of patients had a VAF < 10%. Even in patients with a low VAF for gene mutations, sufficient therapeutic effects were observed with molecular-targeted drugs, suggesting the importance of detecting mutations using a highly sensitive method at initial diagnosis. Further prospective validation studies of a larger number of cases are warranted.

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.

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

This study aimed to identify differentially expressed genes (DEGs) by molecular docking of the hypoxanthine guanine-phosphoribosyl transferase (HGPRT) protein with pulmonary toxins i.e., dibutyl phthalate (DBP) and its metabolites, responsible for the induction of lung cancer. The highest binding affinity of −7.0 kcal/mol obtained was of monobutyl phthalate acyl-A-D-glucuronide. DBP and the protein HGPRT have a strong binding affinity of −7.0 kcal/mol, indicating the possibility of interrupting important biochemical pathways in the treatment of lung cancer. The development of targeted medicines may be guided by this relationship. A total of 120 samples were obtained from the GSE19804 expression profile out of which 60 samples from lung cancer and 60 from normal patients were selected as experimental and control groups. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses elaborated that the gene is involved in purine metabolism, nucleotide metabolism, drug metabolism and the synthesis of several enzymes. The protein–protein interaction (PPI) was assessed using the Search Tool for the Retrieval of Interacting Genes (STRING) database using Cytoscape software. The PPI enrichment [Formula: see text]-value was obtained as &lt;1.0e−16. The docking result of the protein encoded by the AGER gene with DBP was obtained with a minimum binding affinity of up to −6.8 kcal/mol. The soluble receptor for advanced glycation end-products (sRAGE) was found to be involved in inhibiting the activation of oxidative stress and apoptotic pathways. Lung cancer is mostly dependent on the AGER gene and its soluble receptor sRAGE. sRAGE functions as a ruse to counteract the pro-inflammatory effects of AGER signaling and may be a therapeutic target to slow the growth of the malignancy. This study lays the framework for future research and offers novel insights into the role of HGPRT and DBP in the development of lung cancer and targeted therapy.

Gene expression alterations in hypoxic A549 lung cancer cell line.

Human non-small cell lung cancer (NSCLC)is a very common disease with limited treatment options. Hypoxia is a characteristic feature of solid tumors associated with the resistance of cancer cells to radiotherapy and chemotherapy. Therefore, the expression changes in cancer-resistance genes may be biomarkers of hypoxia with value in targeted therapy. The aim of the present study was to examine the effect of hypoxia on gene expression and the changes that occur in relation to drug resistance in a human NSCLC cell line (A549). A549 cells were exposed to 72-h hypoxic episodes (<1% oxygen) for a total of 10 episodes (acute). The alterations in gene expression were examined using PCR array technology after 10 episodes of acute hypoxia and compared with normoxic cells. The chemoresistance of hypoxic cells toward doxorubicin was measured using a MTT cell proliferation assay. A549 cells were affected by acute hypoxia leading to induced doxorubicin chemoresistance. Evident changes in the gene expression level were identified following episodes of acute hypoxia. The most important changes occurred in the estrogen receptor 1 (ESR1) and Finkel-Biskis-Jinkins osteosarcoma (FOS) pathways and in different nucleic transcription factors such as aryl hydrocarbon receptor and cyclin-dependent kinase inhibitor. The present study showed that exposing cells to prolonged periods of hypoxia results in different gene expression changes. There was induction of chemo-resistance due to acute hypoxia. ESR1 and c-FOS are proposed as a potential hypoxia genes in lung cancer.

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.

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.