Risk Of Lung Adenocarcinoma Research Articles

Association between the dietary inflammatory index and risk of lung cancer: a multi-centered case-control study.

Dietary factors might contribute to the risk of lung cancer by increasing the concentration of inflammatory markers. The literature-derived Dietary Inflammatory Index (DII) has been established to evaluate the inflammatory potential of diet correlated with inflammatory markers. The association between DII scores and the risk of lung cancer has been conflicting. So, in the current study, we aimed to assess the effect of pro-inflammatory dietary patterns measured with DII and the risk of lung cancer. A multi-center case-control study was carried out on 616 patients with lung cancer and 3412 healthy controls. Dietary intakes were collected using a 131-item food frequency questionnaire during a face-to-face interview. The DII scores including thirty-six nutrients were calculated after energy adjustments. Finally, the association between DII level and the risk of lung cancer was evaluated by performing a multi-variable regression method after adjusting for potential confounders. The risk of overall lung cancer, small cell, and squamous cell carcinoma was elevated in the third tertile compared to the first tertile of the DII score, (odds ratio [OR] T3 vs. T1 of overall lung cancer = 1.38 (95% confidence interval [CI] 1.08-1.77), P trend = 0.01, OR T3 vs. T1 of squamous cell lung cancer = 1.82 (95% CI 1.02-3.24), P trend = 0.04, OR T3 vs. T1 of small cell lung cancer = 1.66 (95% CI 1.08-2.54), P trend = 0.019). However, no increase was observed in the risk of adenocarcinoma by adherence to a pro-inflammatory dietary pattern. A positive link was found between DII and the risk of overall lung cancer, small-cell, and squamous-cell lung cancer. However, there was no association between DII and the risk of lung adenocarcinoma.

A causal association between chemokines and the risk of lung cancer: a univariate and multivariate mendelian randomization study

BackgroundObservational studies and experimental evidence have shown that chemokines play important roles in lung cancer development, progression, and treatment. However, few studies have examined the causal association between them.MethodsSummary data of chemokines and lung cancer were obtained from genome-wide association studies. Mendelian randomization (MR) analyses were performed by five methods, Inverse variance weighted (IVW), Weighted median estimation, MR-Egger, Simple mode and Weighted, with IVW as the primary analysis method. Sensitivity analysis was used to assess the reliability of the MR results. Multivariate Mendelian randomization studies were used to infer whether causality was influenced by potential mediators. The expression levels of CCL21 were analyzed by quantitative real-time PCR.ResultsWe found that CCL21 was negatively associated with lung adenocarcinoma risk. CCL25 was positively associated with lung squamous cell carcinoma risk. CCL5 was negatively associated with small cell lung cancer risk. CCL21, CCL24, CCL27, and CCL28 was positively associated with small cell lung cancer risk. After multivariate Mendelian randomization adjustment for smoking behavior, it was found that the effect of CCL25 on lung squamous cell cancer disappeared, and the effect of CCL21 on small cell lung cancer was quite opposite to the univariate. The receiver operating characteristic curve indicated that chemokines had high accuracy in the diagnosis of lung cancer. CCL21 expression levels showed large differences in lung adenocarcinoma cells.ConclusionThese results highlighted the causal effects of chemokines on lung cancer and suggested a mediating role of smoking behavior in the association between chemokines and lung cancer.

Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.

Polygenic risk scores (PRSs) are promising for risk stratification but have mainly been developed in European populations. This study developed single- and multi-ancestry PRSs for lung adenocarcinoma (LUAD) in East Asian (EAS) never-smokers using genome-wide association study summary statistics from EAS (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. A multi-ancestry PRS, developed using CT-SLEB, was strongly associated with LUAD risk (odds ratio=1.71, 95% confidence interval (CI):1.61,1.82), with an area under the receiver operating curve value of 0.640 (95% CI:0.629,0.653). Individuals in the highest 20% of the PRS had nearly four times the risk compared to the lowest 20%. Individuals in the 95 th percentile of the PRS had an estimated 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41. Our study underscores the potential of multi-ancestry PRS approaches to enhance LUAD risk stratification in EAS never-smokers.

The association between breast cancer and lung cancer: a bidirectional Mendelian randomization study.

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

Ferroptosis related CPT1A and GDF15 gene polymorphisms are risk factors for lung adenocarcinoma: A case-control study

BackgroundFerroptosis is not only a consequence of inflammation, but also a dynamic process. Recent bioinformatics analysis suggests that ferroptosis related genes might be associated with lung adenocarcinoma (LUAD). CPT1A and GDF15 are critical for the process of ferroptosis and development of inflammation; however, little study focused on the mutation level of these genes in patients with LUAD. MethodsThe candidate SNPs in CPT1A and GDF15 were genotyped in 320 pairs of LUAD patients and controls using Mass ARRAY platform. Moreover, the different expression of CPT1A and GDF15 in LUAD cases and healthy controls were validated by qRT-PCR and ELISA. ResultsThe rs80356779 G > A, rs3019594 C > T, rs888663 T > G and rs4808793 G > C all exhibited an increased risk of the disease (p < 0.05). Moreover, the rs80356779-GA, rs3019594-TT, rs888663-TG and rs4808793-CC genotypes were all related to different levels of increase in LUAD risk (p < 0.05). Genetic model results showed that rs80356779 G > A, rs888663 T > G and rs4808793 G > C were associated with LUAD susceptibility under dominant and additive models (p < 0.05), while rs3019594 C > T was correlated with an elevated risk of the disease in all three models (p < 0.05). Additionally, patients with rs80356779 G > A and rs3019594 C > T exhibited lower expression and serum concentration of CPT1A compared with wile types, and patients with rs888663 T > G and rs4808793 G > C exhibited higher serum and expression level of GDF15. ConclusionThe results provided new clues for the role of ferroptosis in LUAD and new potential targets for screening of susceptible population.

Association between family history with lung cancer incidence and mortality risk in the Asia Cohort Consortium.

Family history of lung cancer (FHLC) has been widely studied but most prospective cohort studies have primarily been conducted in non-Asian countries. We assessed the association between FHLC with risk of lung cancer (LC) incidence and mortality in a population of East Asian individuals. A total of 478,354 participants from 11 population-based cohorts in the Asia Cohort Consortium were included. A Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 7,785 LC incident cases were identified. FHLC (any LC subtype) was associated with an increased risk of LC incidence (HR = 1.45, 95% CI = 1.30-1.63). The positive association was observed in men and women (HR = 1.44, 95% CI = 1.26-1.66 in men; HR = 1.47, 95% CI = 1.22-1.79 in women), and in both never-smokers and ever-smokers (HR = 1.43, 95% CI = 1.18-1.73 in never-smokers; HR = 1.46, 95% CI =1.27-1.67 in ever-smokers). FHLC was associated with an increased risk of lung adenocarcinoma (HR = 1.63, 95% CI: 1.36-1. 94),squamous cell carcinoma (HR = 1.88, 95% CI: 1.46-2.44), and other non-small cell LC (HR = 1.94, 95% CI: 1.02-3.68). However, we found no evidence of significant effect modification by sex, smoking status, and ethnic groups. In conclusion, FHLC was associated with increased risk of LC incidence and mortality, and the associations remained consistent regardless of sex, smoking status and ethnic groups among the East Asian population.

Abstract C167: Understanding the effect of single nucleotide polymorphism rs2292596 on the interaction of aryl hydrocarbon receptor repressor and aryl hydrocarbon receptor nuclear translocator

Abstract Lung cancer is the leading cause of cancer death in America. Additionally, the incident rates among Black/African American (B/AA) men and women are significantly higher than those of their white counterparts, despite B/AA’s lower exposure to cigarette smoke (Berg et al, 2010. Journal of Pharmacology and Experimental Therapeutics, Vol. 332, p202). One factor that may increase the risk of lung adenocarcinoma in B/AA individuals is a single nucleotide polymorphism (SNP) found in the aryl hydrocarbon receptor repressor (AHRR) gene. To date, this SNP has been poorly studied, particularly in B/AA individuals. As its name suggests, AHRR represses the detoxification of tobacco smoke induced by aryl hydrocarbon receptor (AHR). Upon exposure to tobacco smoke, AHR enters the nucleus where it dimerizes with aryl hydrocarbon receptor nuclear translocator (ARNT) and binds to xenobiotic response elements (XREs), thereby inducing the genes mediating the detoxification process. Simultaneously, AHRR is turned on as part of a negative feedback loop. AHRR down-regulates the detoxification process by binding to ARNT, forming a negative regulatory complex that binds to XREs. Within the region of AHRR that encodes for the ARNT interaction domain, a single nucleotide polymorphism (SNP) is found in exon 6. SNP rs2292596 encodes a proline or alanine, with 63% of the White subjects having proline while 89% of the B/AA subjects have proline (Single Nucleotide Polymorphism Database, NCBI). As proline is a turn-inducing amino acid, this change, residing in one of the AHRR loops that encircles ARNT, may affect the kinetics of AHRR/ARNT complex association and/or dissociation, thereby potentially affecting the regulatory balance of detoxification. We are currently synthesizing recombinant AHRR protein containing the two different amino acids, along with ARNT. To assess how these changes in the amino acid sequence affect the interaction of AHRR and ARNT, we will measure the association and dissociation rates using a SwitchSense DRX2 instrument. If the SNP affects the kinetics of AHRR/ARNT heterodimer formation, it may affect detoxification and thereby lung cancer risk. If so, in the future the accuracy of lung cancer detection may be improved by increased screening for individuals carrying the risk allele. Furthermore, if the presence of the risk allele implicates a higher risk for lung cancer, this may strengthen lung cancer prevention within the B/AA community. Funding: This research is supported by R21CA290319 from National Institute of Health (NIH)/National Cancer Institute (NCI), the Norris Comprehensive Cancer Center core grant, award number P30CA014089 from the NIH/NCI, and by the Undergraduate Research Associates Program supported by the USC Provost. Citation Format: Shiori Fukutome, Matthew A. Gladstone, Chunli Yan, Diego A. Velarde, Nicholas Mancuso, Ite Offringa. Understanding the effect of single nucleotide polymorphism rs2292596 on the interaction of aryl hydrocarbon receptor repressor and aryl hydrocarbon receptor nuclear translocator [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C167.

The causal and mediation effect of chronic obstructive pulmonary disease on lung cancer subtypes: a two-sample mendelian randomization study.

This study aims to determine the causal effect of chronic obstructive pulmonary disease (COPD) on different subtypes of lung cancer and to investigate the mediation effects of COPD between smoking and the subtypes of lung cancer. The study utilized summary level data from genome-wide association studies. It extracted independent single nucleotide polymorphisms (SNP) to serve as instrumental variables (IV). We conducted two-sample MR analyses primarily using inverse-variance weighting, as well as MR-Egger and MR-PRESSO to establish and validate the causal impact of COPD on lung cancer subtypes. Additionally, multivariable MR analysis was employed to ascertain the mediating role of COPD between smoking and lung cancers. The two-sample MR analysis demonstrated that COPD is linked to an elevated risk of lung adenocarcinoma (OR: 1.48, 95% CI 1.35-1.61, p = 0.009) and squamous cell carcinoma (OR: 1.78, 95% CI 1.62-1.93, p = 0.001). Further, using multivariable MR, it was established that COPD mediates the causal effects of smoking on lung adenocarcinoma by 56.52% (95% CI 17.51-95.52%) and 63.61% (95% CI 38.31-88.92%) in lung squamous cell carcinoma. Our study found that COPD was a risk factor for developing both lung adenocarcinoma and squamous cell carcinoma. COPD also played a crucial role in mediating the causal effects of smoking on these two subtypes of lung cancer.

Identification of novel pQTL-SNPs associated with lung adenocarcinoma risk: A multi-stage study.

To explore the association between protein quantitative trait loci (pQTL-SNPs) and the risk of LUAD. "Blood +" high depth blood proteomics analysis was performed on plasma from female LUAD patients and female healthy controls, and combined with proteomics data from tumors and adjacent non-tumor tissues of female LUAD patients to screen proteins uniformly expressed in plasma and tissues. pQTL-SNPs were then screened through multiple databases and subjected to multilevel screening. The associations between selected pQTL-SNPs and LUAD risk were evaluated by Female Lung Cancer Consortium in Asia GWAS (FLCCA GWAS). Enzyme linked immunosorbent assay (ELISA) is used to determine the levels of candidate protein. A total of 7 pQTL-SNPs were significantly associated with altered LUAD risk (p < 0.05). Meanwhile, the expression of their corresponding target proteins were all decreased in both plasma and tumor tissues of LUAD cases, which may play a role of tumor suppressor proteins. After mutation of 3 pQTL-SNPs (rs7683000, rs73224660, and rs2776937), the expression of corresponding target proteins BST1 and NRP1 decreased, and as potential tumor suppressor proteins, which may promote tumorigenesis and further increasing the risk of developing LUAD (OR >1, p < 0.05); while after mutation the other pQTL-SNP rs62069916, the corresponding target protein APOH expression was increased, while as a potential tumor suppressor protein, which may inhibit tumorigenesis and further reduced the risk of developing LUAD (OR <1, p < 0.05). In addition, the expression of NRP1 and APOH were significant decreased in LUAD cell lines and validated in plasma of LUAD patients. A total of 4 pQTL-SNPs (rs7683000, rs73224660, rs2776937, and rs62069916) may associate with altered LUAD risk by regulating the expression of target proteins (BST1, NRP1, and APOH) after mutation.

Construction of a pathomics model for predicting mRNAsi in lung adenocarcinoma and exploration of biological mechanism

ObjectiveThis study aimed to predict the level of stemness index (mRNAsi) and survival prognosis of lung adenocarcinoma (LUAD) using pathomics model. MethodsFrom The Cancer Genome Atlas (TCGA) database, 327 LUAD patients were randomly assigned to a training set (n = 229) and a validation set (n = 98) for pathomics model development and evaluation. PyRadiomics was used to extract pathomics features, followed by feature selection using the mRMR-RFE algorithm. In the training set, Gradient Boosting Machine (GBM) was utilized to establish a model for predicting mRNAsi in LUAD. The model's predictive performance was evaluated using ROC curves, calibration curves, and decision curve analysis (DCA). Prognostic analysis was conducted using Kaplan-Meier curves and cox regression. Additionally, gene enrichment analysis, tumor microenvironment analysis, and tumor mutational burden (TMB) analysis were performed to explore the biological mechanisms underlying the pathomics prediction model. ResultsMultivariable cox analysis (HR = 1.488, 95 % CI 1.012–2.187, P = 0.043) identified mRNAsi as a prognostic risk factor for LUAD. A total of 465 pathomics features were extracted from TCGA-LUAD histopathological images, and ultimately, the most representative 8 features were selected to construct the predictive model. ROC curves demonstrated the significant predictive value of the model for mRNAsi in both the training set (AUC = 0.769) and the validation set (AUC = 0.757). Calibration curves and Hosmer-Lemeshow goodness-of-fit test showed good consistency between the model's prediction of mRNAsi levels and the actual values. DCA indicated a good net benefit of the model. The prediction of mRNAsi levels by the pathomics model is represented using the pathomics score (PS). PS was strongly associated with the prognosis of LUAD (HR = 1.496, 95 % CI 1.008–2.222, P = 0.046). Signaling pathways related to DNA replication and damage repair were significantly enriched in the high PS group. Prediction of immune therapy response indicated significantly reduced Dysfunction in the high PS group (P < 0.001). The high PS group exhibited higher TMB values (P < 0.001). ConclusionsThe predictive model constructed based on pathomics features can forecast the mRNAsi and survival risk of LUAD. This model holds promise to aid clinical practitioners in identifying high-risk patients and devising more optimized treatment plans for patients by jointly employing therapeutic strategies targeting cancer stem cells (CSCs).

Inflammatory factors and risk of lung adenocarcinoma: a Mendelian randomization study mediated by blood metabolites.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer, and its pathogenesis remains not fully elucidated. Inflammation and metabolic dysregulation are considered to play crucial roles in LUAD development, but their causal relationships and specific mechanisms remain unclear. This study employed a two-sample Mendelian randomization (MR) approach to systematically evaluate the causal associations between 91 circulating inflammatory factors, 1,400 serum metabolites, and LUAD. We utilized LUAD genome-wide association studies (GWAS) data from the FinnGen biobank and GWAS data of metabolites and inflammatory factors from the GWAS catalog to conduct two-sample MR analyses. For the identified key metabolites, we further used mediator MR to investigate their mediating effects in the influence of IL-17A on LUAD and explored potential mechanisms through protein-protein interaction and functional enrichment analyses. The MR analyses revealed that IL-17A (OR 0.78, 95%CI 0.62-0.99) was negatively associated with LUAD, while 71 metabolites were significantly associated with LUAD. Among them, ferulic acid 4-sulfate may play a crucial mediating role in the suppression of LUAD by IL-17A (OR 0.87, 95%CI 0.78-0.97). IL-17A may exert its anti-LUAD effects through extensive interactions with genes related to ferulic acid 4-sulfate metabolism (such as SULT1A1, CYP1A1, etc.), inhibiting oxidative stress and inflammatory responses, as well as downstream tumor-related pathways of ferulic acid 4-sulfate (such as MAPK, NF-κB, etc.). This study discovered causal associations between IL-17A, multiple serum metabolites, and LUAD occurrence, revealing the key role of inflammatory and metabolic dysregulation in LUAD pathogenesis. Our findings provide new evidence-based medical support for specific inflammatory factors and metabolites as early predictive and risk assessment biomarkers for LUAD, offering important clues for subsequent mechanistic studies and precision medicine applications.

Quantitative parameters of HRCT target scan to predict the risk of lung adenocarcinoma based on the detection of lung ground-glass nodules.

To explore the value of high-resolution computed tomography (HRCT) in the differential diagnosis of benign and malignant ground-glass nodules (GGNs), and to provide a theoretical basis for the clinical application of HRCT. A total of 208 patients with GGN who had been clinically confirmed by surgical pathology and clinical confirmation were collected, and HRCT target scanning technology was used to scan and collect general information of patients, and observe the distribution of GGN, GGN size, GGN cross-sectional area, diameter, transverse diameter, solid composition, relationship with bronchi, and relationship with blood vessels and other indicators. Multivariate regression analysis and risk factor prediction are performed. The differences were statistically significant in multivariate regression analysis, such as nodule location, maximum diameter, maximum cross-sectional area, GGN status, nodule boundary and relationship with blood vessels (P < 0.05). The results of ROC curve showed that the AUC value of nodule site and nodule boundary was greater than 0.5, and the nodule boundary AUC value was 0.676, which was more sensitive to predict whether GGN deteriorated to lung adenocarcinoma (LUAD). Nodule site and nodule boundary are effective risk predictors for LUAD in patients with GGN, and nodule boundary is the most valuable independent predictor.

Crosstalk among Alternative Polyadenylation, Genetic Variants and Ubiquitin Modification Contribute to Lung Adenocarcinoma Risk.

Ubiquitin modification and alternative polyadenylation play crucial roles in the onset and progression of cancer. Hence, this study aims to comprehensively and deeply understand gene regulation and associated biological processes in lung adenocarcinoma (LUAD) by integrating both mechanisms. Alternative polyadenylation (APA)-related E3 ubiquitin ligases in LUAD were identified through multiple databases, and the association between selected genetic loci influencing gene expression (apaQTL-SNPs) and LUAD risk were evaluated through the GWAS database of the Female Lung Cancer Consortium in Asia (FLCCA). Subsequently, the interaction between RNF213 and ZBTB20, as well as their functional mechanisms in LUAD, were investigated using bioinformatics analysis, Western blot, co-immunoprecipitation, and colony formation experiments. A total of five apaQTL-SNPs (rs41301932, rs4494603, rs9890400, rs56066320, and rs41301932), located on RNF213, were significantly associated with LUAD risk (p < 0.05), and they inhibit tumor growth through ubiquitin-mediated degradation of ZBTB20.

The association between human papillomavirus and lung cancer: A Mendelian randomization study

BackgroundTo investigate the causal relationship between human papillomavirus (HPV) and lung cancer, we conducted a study using the two-sample Mendelian randomization (TSMR). MethodData from genome-wide association studies (GWAS) were analyzed with HPV E7 Type 16 and HPV E7 Type 18 as exposure factors. The outcome variables included lung cancer, small cell lung cancer, adenocarcinoma and squamous cell lung cancer. Causality was estimated using inverse variance weighted (IVW), MR-Egger and weighted median methods. Heterogeneity testing, sensitivity analysis, and multiple validity analysis were also performed.. ResultsThe results showed that HPV E7 Type 16 infection was associated with a higher risk of squamous cell lung cancer (OR = 7.69; 95% CI:1.98–29.85; p = 0.0149). HPV E7 Type 18 infection significantly increased the risk of lung adenocarcinoma (OR = 0.71; 95% CI: 0.38–1.31; p = 0.0079) and lung cancer (OR = 7.69; 95% CI:1.98–29.85; p = 0.0292). No significant causal relationship was found between HPV E7 Type 16 and lung adenocarcinoma, lung cancer, or small cell lung carcinoma, and between HPV E7 Type 18 and squamous cell lung cancer or small cell lung carcinoma. ConclusionsThis study has revealed a causal relationship between HPV and lung cancers. Our findings provide valuable insights for further mechanistic and clinical studies on HPV-mediated cancer.

Integrating apaQTL and eQTL analysis identifies a potential causal variant associated with lung adenocarcinoma risk in the Chinese population

Alternative polyadenylation (APA) plays a crucial role in cancer biology. Here, we used data from the 3′aQTL-atlas, GTEx, and the China Nanjing Lung Cancer GWAS database to explore the association between apaQTL/eQTL-SNPs and the risk of lung adenocarcinoma (LUAD). The variant T allele of rs277646 in NIT2 is associated with an increased risk of LUAD (OR = 1.12, P = 0.015), lower PDUI values, and higher NIT2 expression. The 3′RACE experiment showed multiple poly (A) sites in NIT2, with the rs277646-T allele causing preferential use of the proximal poly (A) site, resulting in a shorter 3′UTR transcript. This leads to the loss of the hsa-miR-650 binding site, thereby affecting LUAD malignant phenotypes by regulating the expression level of NIT2. Our findings may provide new insights into understanding and exploring APA events in LUAD carcinogenesis.

TICRR as a potential prognostic biomarker for lung adenocarcinoma: A comprehensive analysis using TCGA database.

To investigate the role of TopBP1-interacting checkpoint and replication regulator (TICRR) in the tumorigenesis and prognosis of lung adenocarcinoma (LUAD) patients. Wilcoxon signed-rank test and logistic regression were utilized to analyze the relationship between clinical characteristics and TICRR expression in LUAD from TCGA dataset. Kaplan-Meier plots and Cox regressions were used to assess the impact of TICRR impact on prognosis. ROC curves and nomograms were generated to further evaluate the relationship between TICRR expression and the risk of LUAD. Gene set enrichment analysis (GSEA) was conducted on TCGA dataset, and ssGSEA was employed to investigate the association between TICRR and immune infiltrates. The results showed that high TICRR expression was significantly associated with various clinical factors including gender, age, pathological stage, T stage, N stage, M stage, outcome of primary therapy and smoking status. ROC curves also demonstrated that TICRR was a promising biomarker for molecular pathology diagnosis in LUAD patients (AUC = 0.952). Further analysis using gene ontology (GO) term enrichment and GSEA revealed an abnormal correlation between TICRR expression and cell division. Interestingly, ssGSEA analysis showed that TICRR expression correlated with multiple immune cell types, such as Th2 cell, TFH cell, mast cell, iDC, eosinophils, and dendritic cell. Lastly, the KM-plotters indicated that LUAD patients with high TICRR expression obtained worse life expectancy (P < .001). TICRR has proven to be a valuable tool in predicting disease progression and prognosis in patients with LUAD, thereby establishing itself as a fitting biomarker for forecasting overall survival (OS) of LUAD patients.

Aging-associated Alterations in the Gene Regulatory Network Landscape Associate with Risk, Prognosis and Response to Therapy in Lung Adenocarcinoma.

Aging is the primary risk factor for many individual cancer types, including lung adenocarcinoma (LUAD). To understand how aging-related alterations in the regulation of key cellular processes might affect LUAD risk and survival outcomes, we built individual (person)-specific gene regulatory networks integrating gene expression, transcription factor protein-protein interaction, and sequence motif data, using PANDA/LIONESS algorithms, for both non-cancerous lung tissue samples from the Genotype Tissue Expression (GTEx) project and LUAD samples from The Cancer Genome Atlas (TCGA). In GTEx, we found that pathways involved in cell proliferation and immune response are increasingly targeted by regulatory transcription factors with age; these aging-associated alterations are accelerated by tobacco smoking and resemble oncogenic shifts in the regulatory landscape observed in LUAD and suggests that dysregulation of aging pathways might be associated with an increased risk of LUAD. Comparing normal adjacent samples from individuals with LUAD with healthy lung tissue samples from those without LUAD, we found that aging-associated genes show greater aging-biased targeting patterns in younger individuals with LUAD compared to their healthy counterparts of similar age, a pattern suggestive of age acceleration. This implies that an accelerated aging process may be responsible for tumor incidence in younger individuals. Using drug repurposing tool CLUEreg, we found small molecule drugs with potential geroprotective effects that may alter the accelerating aging profiles we found. We also observed that, in contrast to chronological age, a network-informed aging signature was associated with survival and response to chemotherapy in LUAD.

The causal effect of atopic dermatitis on lung cancer: A Mendelian randomization study.

Growing evidence has shown that atopic dermatitis (AD) may decrease lung cancer (LC) risk. However, the causality between the two diseases is inconsistent and controversial. Therefore, we explored the causal relationship between AD and different histological subtypes of LC by using the Mendelian randomization (MR) method. We conducted the MR study based on summary statistics from the genome-wide association studies (GWAS) of AD (10,788 cases and 30,047 controls) and LC (29,266 cases and 56,450 controls). Instrumental variables (IVs) were obtained after removing SNPs associated with potential confounders. We employed inverse-variance weighted (IVW), MR-Egger, and weighted median methods to pool estimates, and performed a comprehensive sensitivity analysis. The results of the IVW method suggested that AD may decrease the risk of developing lung adenocarcinoma (LUAD) (OR=0.91, 95% CI: 0.85-0.97, P=0.007). Moreover, no causality was identified between AD and overall LC (OR=0.96, 95% CI: 0.91-1.01, P=0.101), lung squamous cell carcinoma (LUSC) (OR=1.04, 95% CI: 0.96-1.036, P=0.324), and small cell lung carcinoma (SCLC) (OR=0.95, 95% CI: 0.82-1.10, P=0.512). A comprehensive sensitivity test showed the robustness of our results. The present study indicates that AD may decrease the risk of LUAD in the European population, which needs additional investigations to identify the potential molecular mechanisms.

Causal association of circulating cytokines with the risk of lung cancer: a Mendelian randomization study.

Lung cancer is the deadliest and most prevalent malignancy worldwide. While smoking is an established cause, evidence to identify other causal factors remains lacking. Current research indicates chronic inflammation is involved in tumorigenesis and cancer development, though the specific mechanisms underlying the role of inflammatory cytokines in lung cancer pathogenesis remain unclear. This study implemented Mendelian randomization (MR) analysis to investigate the causal effects of circulating cytokines on lung cancer development. We performed a two-sample MR analysis in Europeans utilizing publicly available genome-wide association study summary statistics. Single nucleotide polymorphisms significantly associated with cytokine were selected as genetic instrumental variables. Genetically predicted levels of the chemokine interleukin-18 (IL-18) (OR = 0.942, 95% CI: 0.897-0.990, P = 0.018) exerted significant negative causal effects on overall lung cancer risk in this analysis. Examining specific histologic subtypes revealed further evidence of genetic associations. Stem cell factor (SCF) (OR = 1.150, 95% CI: 1.021-1.296, P = 0.021) and interleukin-1beta (IL-1β) (OR = 1.152, 95% CI: 1.003-1.325, P = 0.046) were positively associated with lung adenocarcinoma risk, though no inflammatory factors showed causal links to squamous cell lung cancer risk. Stratified by smoking status, interferon gamma-induced protein 10 (IP-10) (OR = 0.861, 95% CI: 0.781-0.950, P = 0.003) was inversely associated while IL-1β (OR = 1.190, 95% CI: 1.023-1.384, P = 0.024) was positively associated with lung cancer risk in ever smokers. Among never smokers, a positive association was observed between lung cancer risk and SCF (OR = 1.474, 95% CI: 1.105-1.964, P = 0.008). Importantly, these causal inferences remained robust across multiple complementary MR approaches, including MR-Egger, weighted median, weighted mode and simple mode regressions. Sensitivity analyses also excluded potential bias stemming from pleiotropy. This MR study found preliminary evidence that genetically predicted levels of four inflammatory cytokines-SCF, IL-1β, IL-18, and IP-10-may causally influence lung cancer risk in an overall and subtype-specific manner, as well as stratified by smoking status. Identifying these cytokine pathways that may promote lung carcinogenesis represents potential new targets for the prevention, early detection, and treatment of this deadly malignancy.

Association of CCND1 rs9344 polymorphism with lung cancer susceptibility and clinical outcomes: a case-control study.

Cyclin D1 (CCND1) plays a pivotal role in cancer susceptibility and the platinum-based chemotherapy response. This study aims to assess the relationship between a common polymorphism (rs9344 G > A) in CCND1 gene with cancer susceptibility, platinum-based chemotherapy response, toxicities and prognosis of patients with lung cancer. This study involved 498 lung cancer patients and 213 healthy controls. Among them, 467 patients received at least two cycles of platinum-based chemotherapy. Unconditional logistical regression analysis and meta-analysis were performed to evaluate the associations. The lung adenocarcinoma risk was significantly higher in patients with AA than GG + GA genotype (adjusted OR = 1.755, 95%CI = 1.057-2.912, P = 0.030). CCND1 rs9344 was significantly correlated with platinum-based therapy response in patients receiving PP regimen (additive model: adjusted OR = 1.926, 95%CI = 1.029-3.605, P = 0.040; recessive model: adjusted OR = 11.340, 95%CI = 1.428-90.100, P = 0.022) and in the ADC subgroups (recessive model: adjusted OR = 3.345, 95%CI = 1.276-8.765, P = 0.014). Furthermore, an increased risk of overall toxicity was found in NSCLC patients (additive model: adjusted OR = 1.395, 95%CI = 1.025-1.897, P = 0.034; recessive model: adjusted OR = 1.852, 95%CI = 1.088-3.152, P = 0.023), especially ADC subgroups (additive model: adjusted OR = 1.547, 95%CI = 1.015-2.359, P = 0.043; recessive model: adjusted OR = 2.030, 95%CI = 1.017-4.052, P = 0.045). Additionally, CCND1 rs9344 was associated with an increased risk of gastrointestinal toxicity in non-smokers (recessive model: adjusted OR = 2.620, 95%CI = 1.083-6.336, P = 0.035). Non-significant differences were observed in the 5-year overall survival rate between CCND1 rs9344 genotypes. A meta-analysis of 5432 cases and 6452 control samples did not find a significant association between lung cancer risk and CCND1 rs9344 polymorphism. This study suggests that in the Chinese population, CCND1 rs9344 could potentially serve as a candidate biomarker for cancer susceptibility and treatment outcomes in specific subgroups of patients.