Risk Of Lung Adenocarcinoma Research Articles

Programmed Death Ligand 2 Gene Polymorphisms Are Associated With Lung Adenocarcinoma Risk in Female Never-Smokers.

ObjectivesLung cancer in never-smokers is a distinct disease associated with a different genomic landscape, pathogenesis, risk factors, and immune checkpoint inhibitor responses compared to those observed in smokers. This study aimed to identify novel single nucleotide polymorphisms (SNPs) of programmed death-1 (encoded by PDCD1) and its ligands, programmed death ligand 1 (CD274) and 2 (PDCD1LG2), associated with lung cancer risk in never-smoking women.Materials and MethodsDuring September 2002 and July 2012, we enrolled never-smoking female patients with lung adenocarcinoma (LUAD) (n=1153) and healthy women (n=1022) from six tertiary hospitals in Taiwan. SNP data were obtained and analyzed from the genome-wide association study dataset and through an imputation method. The expression quantitative trait loci (eQTL) analysis was performed in both tumor and non-tumor tissues for the correlation between genetic expression and identified SNPs.ResultsA total of 12 PDCD1LG2 SNPs related to LUAD risk were identified in never-smoking women, including rs2381282, rs4742103, rs4237162, rs4742104, rs12237624, rs78096119, rs6476988, rs7857315, rs10975178, rs7854413, rs56001683, and rs7858319. Among them, six tagged PDCD1LG2 SNPs rs2381282, rs4742103, rs4237162, rs4742104, rs78096119, and rs56001683 were significantly associated with LUAD risk. Specifically, two PDCD1LG2 SNPs, rs12237624 and rs78096119, were associated with previous pulmonary tuberculosis infection in relation to LUAD susceptibility. Through an eQTL assay, we found that rs2381282 (p < 0.001), rs12237624 (p = 0.019), and rs78096119 (p = 0.019) were associated with the expression levels of programed death ligand 2.ConclusionsNovel SNPs of programed death ligand 2 associated with lung adenocarcinoma risk were identified. Among them, two SNPs were associated with pulmonary tuberculosis infection in relation to lung adenocarcinoma susceptibility. These SNPs may help to stratify high-risk populations of never-smokers during lung cancer screening.

High CTSL2 expression predicts poor prognosis in patients with lung adenocarcinoma

Cathepsin like 2 (CTSL2) is a lysosomal cysteine protease, and may be associated with tumor metastasis. However, CTSL2 has not been reported as a biomarker in lung adenocarcinoma (LUAD). In this study, bioinformatics analysis using data from The Cancer Genome Atlas was performed. Wilcoxon rank-sum test and chi-square test were carried out. Kaplan-Meier and Cox regression were performed to evaluate the effect of CTSL2 expression in the overall survival. Our results indicated that CTSL2 in tumor was significantly higher than that in normal tissue (P < 0.001). High CTSL2 expression was significantly associated with age (P = 0.02), vital status (P < 0.001), and T classification (P = 0.03), and correlated with poor overall survival (HR = 1.62, 95% CI = 1.21–2.18, P = 0.001). CTSL2 expression was an independent risk factor for overall survival in patients with LUAD (HR = 1.52, 95% CI = 1.12–2.05, P = 0.006). A nomogram was plotted for illustration of CTSL2 expression on the risk of LUAD. Furthermore, in vitro cell experiments showed the CTSL2 promoted the proliferation and migration of A549 cells. In summary, high CTSL2 expression predicts poor prognosis in patients with LUAD.

Construction and Validation of Prognostic Risk Score Model of Autophagy Related Genes in Lung Adenocarcinoma

背景与目的自噬相关基因(autophagy related genes, ARGs)可调控溶酶体的降解过程从而诱导细胞发生自噬，参与多种癌症的发生发展，肿瘤组织中ARGs的表达情况在预测患者生存方面具有很大的前景。本研究基于ARGs构建了肺腺癌(lung adenocarcinoma, LUAD)预后风险评分模型。方法通过GeneCards数据库获得5, 786个ARGs。从癌症基因组图谱(The Cancer Genome Atlas, TCGA)数据库收集了395个LUAD患者的基因表达谱及临床数据，提取所有ARGs的表达数据，利用R软件筛选差异表达的ARGs。对差异表达的ARGs进行生存分析，筛选有预后价值的ARGs并进行功能富集分析。利用套索(the least absolute shrinkage and selection operator, LASSO)回归和Cox回归模型构建ARGs的预后风险评分模型。绘制受试者工作特征曲线(receiver operating characteristic curve，ROC曲线)得到风险评分的最佳cut-off值，将患者分为高风险评分组和低风险评分组。计算ROC曲线下面积(area under curve, AUC)和绘制Kaplan-Meier生存曲线评估模型性能，并在外部数据集验证。最后利用单因素和多因素Cox回归分析评价模型是否具有独立预后价值，并分析其临床相关性。结果通过生存分析初步筛选了52个与预后相关的ARGs，以此为基础，利用LASSO回归和Cox回归分析构建了由5个ARGs(ADAM12、CAMP、DKK1、STRIP2和TFAP2A)组成的LUAD预后风险评分模型。该模型中，低风险评分组患者的生存时间明显优于高风险评分组(P < 0.001)，且在训练集(AUCmax=0.78)和两个外部验证集(AUCmax=0.88)中均展现出良好的预测性能。风险评分在单因素和多因素Cox回归分析中与LUAD患者预后显著相关(P < 0.001)，提示风险评分可作为LUAD潜在的独立预后因素。临床特征相关性分析表明高风险评分与高T分期、高肿瘤分期和发生不良预后密切相关。结论我们构建了一个由5个ARGs组成的LUAD风险评分模型，该模型可为预测LUAD患者预后提供参考，未来或可与恶性肿瘤(tumor node metastasis, TNM)分期联合应用于肺腺癌患者的预后预测。

An N6-Methyladenosine-Related Gene Set Variation Score as a Prognostic Tool for Lung Adenocarcinoma.

N6-methyladenosine (m6A) is the most prevalent type of RNA modification, and we hypothesized that patterns of m6A-related genes may be useful for estimating risk of lung adenocarcinoma (LUAD). An m6A-related gene set variation score (m6A-GSVS) was generated using RNA-sequencing data from LUAD patients in The Cancer Genome Atlas (TCGA). We investigated the association of m6A-GSVS with stemness, tumor mutational burden (TMB), expression of three immune checkpoints, levels of tumor-infiltrating lymphocytes (TILs), and patient prognosis. We found that m6A-GSVS was higher in LUAD than in healthy lung tissue, and it strongly correlated with stemness and TMB. Activated CD4 + T cells were more numerous in LUAD samples that had higher m6A-GSVS than in those with lower scores. Biological processes and pathways, including “Cell cycle,” “DNA replication,” and “RNA degradation,” were significantly enriched in samples with high scores. Furthermore, m6A-GSVS was an independent prognostic indicator in LUAD. In conclusion, we proposed an m6A-GSVS in LUAD. It is a putative indicator for evaluating the ability to RNA m6A, an independent prognostic indicator and associated with tumor stemness.

Identification of a Ferroptosis-Related LncRNA Signature as a Novel Prognosis Model for Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is a highly heterogeneous malignancy, which makes prognosis prediction of LUAD very challenging. Ferroptosis is an iron-dependent cell death mechanism that is important in the survival of tumor cells. Long non-coding RNAs (lncRNAs) are considered to be key regulators of LUAD development and are involved in ferroptosis of tumor cells, and ferroptosis-related lncRNAs have gradually emerged as new targets for LUAD treatment and prognosis. It is essential to determine the prognostic value of ferroptosis-related lncRNAs in LUAD. In this study, we obtained RNA sequencing (RNA-seq) data and corresponding clinical information of LUAD patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database and ferroptosis-related lncRNAs by co-expression analysis. The best predictors associated with LUAD prognosis, including C5orf64, LINC01800, LINC00968, LINC01352, PGM5-AS1, LINC02097, DEPDC1-AS1, WWC2-AS2, SATB2-AS1, LINC00628, LINC01537, LMO7DN, were identified by Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis, and the LUAD risk prediction model was successfully constructed. Kaplan-Meier analysis, receiver operating characteristic (ROC) time curve analysis and univariate and multivariate Cox regression analysis and further demonstrated that the model has excellent robustness and predictive ability. Further, based on the risk prediction model, functional enrichment analysis revealed that 12 prognostic indicators involved a variety of cellular functions and signaling pathways, and the immune status was different in the high-risk and low-risk groups. In conclusion, a risk model of 12 ferroptosis related lncRNAs has important prognostic value for LUAD and may be ferroptosis-related therapeutic targets in the clinic.

Association between Sleep Traits and Lung Cancer: A Mendelian Randomization Study.

Multidimensional sleep trait, which is related to circadian rhythms closely, affects some cancers predominantly, while the relationship between sleep and lung cancer is rarely illustrated. We aimed to investigate whether sleep is causally associated with risk of lung cancer, through a two-sample Mendelian randomization study. The main analysis used publicly available GWAS summary data from two large consortia (UK Biobank and International Lung Cancer Consortium). Two-sample Mendelian randomization (MR) analysis was used to examine whether chronotype, getting up in the morning, sleep duration, nap during the day, or sleeplessness was causally associated with the risk of lung cancer. Additionally, multivariate MR analysis was also conducted to estimate the direct effects between sleep traits and lung cancer risks independent of smoking status including pack years of smoking or current tobacco smoking. There was no evidence of causal association between chronotype, getting up in the morning, or nap during the day and lung cancer. Sleeplessness was associated with higher risk of lung adenocarcinoma (odds ratio 5.75, 95% confidence intervals 2.12-15.65), while sleep duration played a protective role in lung cancer (0.46, 0.26-0.83). In multivariate MR analysis, sleeplessness and sleep duration remained to have similar results. In conclusion, we found robust evidence for effect of sleeplessness on lung adenocarcinoma risk and inconsistent evidence for a protective effect of sleep duration on lung cancer risk.

N6-Methyladenosine RNA Methylation Regulator-Related Alternative Splicing (AS) Gene Signature Predicts Non-Small Cell Lung Cancer Prognosis.

Aberrant N6-methyladenosine (m6A) RNA methylation regulatory genes and related gene alternative splicing (AS) could be used to predict the prognosis of non–small cell lung carcinoma. This study focused on 13 m6A regulatory genes (METTL3, METTL14, WTAP, KIAA1429, RBM15, ZC3H13, YTHDC1, YTHDC2, YTHDF1, YTHDF2, HNRNPC, FTO, and ALKBH5) and expression profiles in TCGA-LUAD (n = 504) and TCGA-LUSC (n = 479) datasets from the Cancer Genome Atlas database. The data were downloaded and bioinformatically and statistically analyzed, including the gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. There were 43,948 mRNA splicing events in lung adenocarcinoma (LUAD) and 46,020 in lung squamous cell carcinoma (LUSC), and the data suggested that m6A regulators could regulate mRNA splicing. Differential HNRNPC and RBM15 expression was associated with overall survival (OS) of LUAD and HNRNPC and METTL3 expression with the OS of LUSC patients. Furthermore, the non–small cell lung cancer prognosis-related AS events signature was constructed and divided patients into high- vs. low-risk groups using seven and 14 AS genes in LUAD and LUSC, respectively. The LUAD risk signature was associated with gender and T, N, and TNM stages, but the LUSC risk signature was not associated with any clinical features. In addition, the risk signature and TNM stage were independent prognostic predictors in LUAD and the risk signature and T stage were independent prognostic predictors in LUSC after the multivariate Cox regression and receiver operating characteristic analyses. In conclusion, this study revealed the AS prognostic signature in the prediction of LUAD and LUSC prognosis.

Reproductive Factors and Lung Cancer Risk among Never-Smoking Japanese Women with 21 Years of Follow-Up: A Cohort Study.

Previous studies have reported inconsistent associations between reproductive factors and lung cancer. We used data from the Japan Public Health Center-based Prospective Study, which included 400 incident lung cancer cases (305 adenocarcinoma) among 42,615 never-smoking women followed for a median of 21 years, to examine the associations of reproductive and hormonal factors with lung cancer by histological type using Cox proportional hazards models. Longer fertility span (≥36 years vs. ≤32 years) was associated with increased risk of lung adenocarcinoma (HR, 1.48; 95% CI, 1.07-2.06, P trend = 0.01) but not with all lung cancer or nonadenocarcinoma. Similarly, late age at menopause (≥ 50 years) was associated with increased adenocarcinoma risk (vs. ≤ 47 years, HR, 1.41; 95% CI, 1.01-1.96, P trend 0.04). Compared with premenopausal women, women with natural menopause (HR, 1.99; 95% CI, 1.02-3.88) or surgical menopause (HR, 2.75; 95% CI, 1.33-5.67) were at increased risk of adenocarcinoma. In contrast, breastfeeding was associated with reduced risk of nonadenocarcinoma (HR, 0.51; 95% CI, 0.28-0.92). No significant association with parity, age at first birth, exogenous hormone use, or length of menstrual cycle was detected. Reproductive factors may play a role in lung carcinogenesis. Future studies that include estrogen and progesterone biomarkers may help clarify the role of endogenous hormones in lung carcinogenesis. Fertility span and age at menopause may be useful variables in developing risk prediction models for lung adenocarcinoma among nonsmoking women.

Rheumatoid arthritis and risk of lung cancer: Meta-analysis and Mendelian randomization study

ObjectiveObservational studies suggest that rheumatoid arthritis (RA) may be associated with lung cancer (LC) risk, while the evidence is inconsistent. We conducted a meta-analysis and a Mendelian randomization study to investigate the association and causality between RA and the LC risk. MethodsWe conducted a systematic search of cohort studies and performed a meta-analysis (PROSPERO ID CRD42020159082) to calculate the relative risks (RRs) and their 95% confidence intervals (95%CIs). Subgroup analyses based on sex and initiation year of follow-up were carried out. E‐values of each study were calculated to evaluate if existing studies were sensitive to unmeasured confounding. Furthermore, we investigated the correlation between genetically predisposed RA and LC risk using summary statistics from the International Lung Cancer Consortium (11,348 cases and 15,861 controls) and 90 RA-related single nucleotide polymorphisms from European and East Asian descent as instrumental variables. A two-sample Mendelian randomization (MR) analysis was performed to detect the findings based on LC and histological subtypes. Sensitivity analyses were performed to test the robustness of our findings. ResultsIn the meta-analysis of 11 cohort studies involving 183,888 patients, an increased risk of LC was observed among RA patients (RR = 1.44, 95%CI = 1.31–1.57). Subgroup analyses suggested that male patients have a relatively higher LC risk than female patients, and an increased incidence of LC in RA patients was found from 1950 to 2010. Conversely, in the MR analysis, we found that genetically predisposed RA was associated with a decreased risk of LC overall, while neither causally associated with the risk of lung adenocarcinoma nor squamous cell lung cancer. Nevertheless, genetically predisposed RA was associated with a decreased LC risk among the East Asian population, but not in Europeans. These results were robust against extensive sensitivity analyses. ConclusionOur meta-analysis suggested that although RA was associated with a relatively higher LC risk, the causal relationship between genetically predisposed RA and LC risk was not supported by the MR study. Further studies are warranted to elucidate the possible association between RA and the risk of LC, as well as its underlying mechanisms.

PL01.06 Molecular Epidemiology of Asian Lung Cancer

Lung adenocarcinoma (LADC), the most frequent histological type of lung cancer, develops in both ever- and never-smokers, and has two distinct characteristics in Asian populations. First, the proportion of never-smoking patients is considerably higher than that among individuals of European descent (approximately 40% vs 10%), and the rates of development and death from lung cancer in never-smokers are significantly higher in Asians than those in individuals of European descent. Second, in Asian individuals LADC frequently (in approximately 50% of cases) carries oncogenic mutations of the epidermal growth factor receptor (EGFR) gene, in contrast to lower EGFR mutation rates (approximately 10%) in European/US patients. In Asian patients, EGFR mutation frequently occurs in both never- (60%) and ever- (40%) smokers, while it occurs almost exclusively in European/US ever-smokers. Notably, EGFR-mutated LADC does not respond well to immune checkpoint blockade therapy due to its non-inflamed (immune-cold) features, including low infiltration of CD4+ and CD8+ T cells. Therefore, it is highly likely that there are specific risk factors, independent from smoking, that promote LADC development in Asians and have immunogenic effects influencing tumour characteristics. By conducting genome-wide association study, we demonstrated that HLA loci influence lung adenocarcinoma risk independently from smoking and that the association of HLA-class II, but not class I, loci is more prominent for lung adenocarcinomas with EGFR gene mutations than those without; the HLA-DPB1 Asp57 and 76Val alleles are associated with elevated risk for EGFR-mutated lung adenocarcinoma. HLA variants might influence lung adenocarcinoma risk by modulating anti-tumour immunity.

Gene signatures of 6-methyladenine regulators in women with lung adenocarcinoma and development of a risk scoring system: a retrospective study using the cancer genome atlas database.

Although the emergence of new treatments has improved the prognosis of women with lung adenocarcinoma (LUAD), the emergence of drug resistance limits their clinical efficacy. Therefore, there is an urgent need to identify new targets and develop a risk scoring system to evaluate the prognosis of patients. 6-methyladenine (M6A), as the most common methyl modification in RNA modification, its clinicopathological features, diagnosis and prognostic value in lung cancer, especially in LUAD remain to be discussed. We analyzed the clinical and sequencing data of the female LUAD cohort from The Cancer Genome Atlas (TCGA), evaluated the expression profiles of 16 M6A regulation-related genes in the cohort and the relationships between genetic changes and clinical characteristics, developed an M6A-related risk scoring system using Cox analysis. Finally, the copy number variations (CNVs) of the related genes in the samples were analyzed and verified using the cBioPortal platform. Compared with other clinical factors, this risk scoring system showed a higher predictive sensitivity and specificity. The M6A-related risk scoring system developed in this study may help to improve the screening of female patients at high risk of LUAD and provides important theoretical bioinformatics support for evaluating the prognosis of such patients.

XXYLT1 methylation contributes to the occurrence of lung adenocarcinoma: Methylation and lung adenocarcinoma.

Background:There is evidence that DNA methylation play major roles in lung cancer. In our previously study, C3 or f21 , also referred to as XXYLT1, rs2131877 polymorphism is associated with a reduced risk of lung adenocarcinoma. So, we explored the role of XXYLT1 methylation in lung adenocarcinoma.Methods:This study was conducted in 2 steps. In the first step, we recruited 15 patients with lung adenocarcinoma. Cancer tissues and para-carcinoma tissues were obtained from each of the patients. In the second step, 150 patients with lung adenocarcinom were enrolled, and cancer and normal lung tissue were obtained from each patients, respectively. The expression levels of XXYLT1 mRNA were determined, the deoxyribonucleic acid methylation status was analyzed by MassARRAY Spectrometry. The methylation data of individual units were generated by EpiTyper v1.0.5 software.Results:The XXYLT1 mRNA expression was significantly lower in cancer tissues than in para-carcinoma and normal lung tissues. Meanwhile, the methylation rates of three CpG units (CpG_23, CpG_25, and CpG_60.61.62.63.64.65) within the XXYLT1 gene were higher in cancer tissues compared to the para-carcinoma and the normal lung tissues. This difference was particularly significant in male patients.Conclusions:Our results suggested that methylation of XXYLT1 may have significance in the pathogenesis of lung adenocarcinoma.

Contribution of XPD and XPF Polymorphisms to Susceptibility of Non-Small Cell Lung Cancer in High-Altitude Areas

Background: We aimed to explore the relation of XPD and XPF variants with non-small cell lung cancer (NSCLC) risk and the effect of these variants on the sensitivity to cisplatin-based chemotherapy among the Chinese Han population in high-altitude areas. Methods: Eight single-nucleotide polymorphisms (SNPs) in XPD and XPF were genotyped by Agena MassARRAY platform among 506 NSCLC cases and 510 healthy controls. Correlation of XPD and XPF gene polymorphisms with NSCLC susceptibility and the response of cis­platin-based chemotherapy were analyzed with logistic regression by calculating odds ratios (ORs) and 95% confidence intervals (CIs). Results: XPD rs13181 (OR = 1.53, 95% CI: 1.04–2.24, p = 0.029) and rs1052555 (OR = 1.63, 95% CI: 1.05–2.53, p = 0.029) possibly contributed to the increased risk of lung adenocarcinoma, while XPD rs238406 (OR = 0.63, 95% CI: 0.43–0.94, p = 0.024) was a protective factor for lung squamous cell carcinoma. Age, gender, BMI, smoking, and drinking might affect the correlation of XPD and XPF polymorphisms with NSCLC risk. More importantly, XPD rs13181 (OR = 2.91, p = 0.015), XPD rs1052555 (OR = 2.67, p = 0.022), and XPF rs231127 (OR = 4.15, p = 0.008) were associated with treatment response in NSCLC patients underwent cisplatin-based chemotherapy. Conclusion: This study found that XPD and XPF variants might contribute to NSCLC risk and the response of cisplatin-based chemotherapy among the Chinese Han population in high-altitude areas.

Influence of CMTM8 polymorphisms on lung cancer susceptibility in the Chinese Han population.

Lung cancer is the leading cause of cancer-related mortality worldwide and CMTM8 is a potential tumor suppressor gene, which is down-regulated in lung cancer. The objective of this research was to assess the association of CMTM8 genetic polymorphisms with lung cancer risk. To evaluate the correlation between CMTM8 polymorphisms and lung cancer risk, Agena MassArray platform was used for genotype determination among 509 lung cancer patients and 506 controls. Multiple genetic models, stratification analysis and Haploview analysis were used by calculating odds ratio (OR) and 95% confidence intervals (CIs). Significant associations were detected between CMTM8 rs6771238 and an increased lung cancer risk in codominant (adjusted OR = 1.57, 95% CI: 1.01-2.42, P = 0.044) and dominant (adjusted OR = 1.54, 95% CI: 1.01-2.36, P = 0.047) models. After sex stratification analysis, we observed that rs6771238 was related to an increased risk of lung squamous cell carcinoma, while rs6771238 was associated with an increased risk of lung adenocarcinoma. Rs9835916 was linked to increased risk of lymph node metastasis in lung cancer patients. Our study first reported that CMTM8 polymorphisms were a risk factor for lung cancer, which suggested the potential roles of CMTM8 in the development of lung cancer.

High expression of RRM2 as an independent predictive factor of poor prognosis in patients with lung adenocarcinoma.

Ribonucleotide reductase subunit M2 may play a role as a potential prognostic biomarker in several cancers. In this study, we evaluated whether RRM2 gene expression is associated with the prognosis of patients with lung adenocarcinoma (LUAD) using publicly available data from The Cancer Genome Atlas (TCGA). Wilcoxon signed-rank test and logistic regression were performed to evaluate the association between RRM2 expression and clinical features in patients with LUAD. Kaplan-Meier and Cox regression methods were used to examine the effect of RRM2 expression level in the overall survival, and a nomogram was performed to illustrate the correlation between the RRM2 gene expression and the risk of LUAD. TCGA data set was used for gene set enrichment analysis (GSEA). We also performed a further experiment in vitro to assess the effect of RRM2 expression on the proliferation and invasive abilities of LUAD cells and its key signaling pathway proteins. Our results revealed that the expression level of RRM2 in patients with LUAD was much higher than that in normal tissues (p = 3.99e-32). High expression of RRM2 was significantly associated with tumor stage (IV vs. I: OR = 3.02, p = 0.012) and TNM classification (T2 vs. T1: OR = 1.88, p = 0.001; N2 vs. N0: OR = 2.69, p < 0.001). Kaplan-Meier survival analysis showed that high expression of RRM2 was associated with a worse prognosis of LUAD compared low expression of RRM2 (p = 7.86e-04). Multivariate analysis showed that high RRM2 expression was an independent factor affecting overall survival (HR = 1.29, p < 0.001). The association between RRM2 gene expression and the risk of LUAD was presented in a nomogram. GSEA revealed that the cell cycle, p53 signaling pathway, DNA replication, small cell lung cancer, apoptosis, and pathways in cancer were differentially enriched in patients with high expression of RRM2. RRM2 over-expression promoted the proliferation and invasive abilities of LUAD cells. RRM2 over-expression increased the activation of Bcl-2 and E-cadherin signaling pathways, and reduced the activation of p53 signaling pathway. In summary, high RRM2 expression is an independent predictive factor of poor prognosis in patients with lung adenocarcinoma.

Inherited Rare, Deleterious Variants in ATM Increase Lung Adenocarcinoma Risk.

Lung cancer is the leading cause of cancer deaths in the world, and lung adenocarcinoma (LUAD) is its most prevalent subtype. Symptoms are often found in advanced disease in which treatment options are limited. Identifying genetic risk factors will enable better identification of high-risk individuals. To identify LUAD risk genes, we performed a case-control association study for gene-level burden of rare, deleterious variants (RDVs) in germline whole-exome sequencing data of 1083 patients with LUAD and 7650 controls, split into discovery and validation cohorts. Of these, we performed whole-exome sequencing on 97 patients and acquired the rest from multiple public databases. We annotated all rare variants for pathogenicity conservatively, using the guidelines of the American College of Medical Genetics and Genomics and ClinVar curation, and investigated gene-level RDV burden using penalized logistic regression. All statistical tests were two-sided. We discovered and replicated the finding that the burden of germline ATM RDVs was significantly higher in patients with LUAD versus controls (combined cohort OR= 4.6; p= 1.7e-04; 95% confidence interval= 2.2-9.5; 1.21% of cases; 0.24% of controls). Germline ATM RDVs were also enriched in an independent clinical cohort of 1594 patients from the MSK-IMPACT study (0.63%). In addition, we observed that an Ashkenazi Jewish (AJ) founder ATM variant, rs56009889, was statistically significantly more frequent in AJ cases versus AJ controls in our cohort (combined AJ cohort OR= 2.7, p= 6.9e-03, 95% confidence interval= 1.3-5.3). Our results indicate that ATM is a moderate-penetrance LUAD risk gene and that LUAD may be a part of the ATM-related cancer syndrome spectrum. Individuals with ATM RDVs are at an elevated LUAD risk and can benefit from increased surveillance (particularly computed tomography scanning), early detection, and chemoprevention programs, improving prognosis.

Eight-gene signature predicts recurrence in lung adenocarcinoma.

Recurrence significantly influences the survival in patients with lung adenocarcinoma (LUAD). However, there are less gene signatures that predict recurrence risk of LUAD. We performed this study to construct a model to predict risk of recurrence in LUAD. RNA-seq data from 426 patients with LUAD were downloaded from The Cancer Genome Atlas (TCGA) and were randomly assigned into the training (n= 213) and validation set (n= 213). Differentially expressed genes (DEGs) between recurrent and non-recurrent tumors in the training set were identified. Recurrence-associated DEGs were selected using multivariate Cox regression analysis. The recurrence risk model that identifies patients at low and high risk for recurrence was constructed, followed by the validation of its performance in the validation set and a microarray dataset. In total, 378 DEGs, including 20 recurrence-associated DEGs, were identified between the recurrent and non-recurrent tumors in the training set. The signatures of 8 genes (including AZGP1, INPP5J, MYBPH, SPIB, GUCA2A, HTR1B, SLC15A1 and TNFSF11) were used to construct the prognostic model to assess the risk of recurrence. This model indicated that patients with high risk scores had shorter recurrence-free survival time compared with patients with low risk scores. ROC curve analysis of this model showed it had high predictive accuracy (AUC > 0.8) to predict LUAD recurrence in the TCGA cohort (the training and validation sets) and GSE50081 dataset. This prognostic model showed high predictive power and performance in predicting recurrence in LUAD. We concluded that this model might be of great value for evaluating the risk of recurrence of LUAD in clinics.

FGFR4 Gene Polymorphism Reduces the Risk of Distant Metastasis in Lung Adenocarcinoma in Taiwan.

Fibroblast growth factor receptor 4 (FGFR4) is involved in multiple physiological and pathological processes. Several genetic variants of FGFR4 have been shown to be associated with tumor progression in many cancers. However, its association, such as genetic variants and expression levels, with lung cancer is controversial. The present study examined the relationship between four single-nucleotide polymorphisms (SNPs; rs2011077 T/C, rs351855 G/A, rs7708357 G/A, and rs1966265 A/G) of FGFR4 and the risk of lung adenocarcinoma with the epidermal growth factor receptor (EGFR) mutation status in a Taiwanese cohort. The results demonstrated that FGFR4 rs2011077 (odds ratio (OR) = 0.348, 95% confidence interval (CI) = 0.136–0.891, p = 0.024), and rs351855 (OR = 0.296, 95% CI = 0.116–0.751, p = 0.008) showed an inverse association with distant metastasis in wild-type EGFR lung adenocarcinoma. Furthermore, a database analysis using The Cancer Genome Atlas revealed that the higher FGFR4 expression level was correlated with poor survival rates in wild-type EGFR lung adenocarcinoma. In conclusion, the data suggest that FGFR4 SNPs may help in identifying patient subgroups at low-risk for tumor metastasis, among carriers of lung adenocarcinoma bearing wild-type EGFR.

Support Vector Machine for Lung Adenocarcinoma Staging Through Variant Pathways.

Lung adenocarcinoma (LUAD) is one of the most common malignant tumors. How to effectively diagnose LUAD at an early stage and make an accurate judgement of the occurrence and progression of LUAD are still the focus of current research. Support vector machine (SVM) is one of the most effective methods for diagnosing LUAD of different stages. The study aimed to explore the dynamic change of differentially expressed genes (DEGs) in different stages of LUAD, and to assess the risk of LUAD through DEGs enriched pathways and establish a diagnostic model based on SVM method. Based on TMN stages and gene expression profiles of 517 samples in TCGA-LUAD database, coefficient of variation (CV) combined with one-way analysis of variance (ANOVA) were used to screen out feature genes in different TMN stages after data standardization. Unsupervised clustering analysis was conducted on samples and feature genes. The feature genes were analyzed by Pearson correlation coefficient to construct a co-expression network. Fisher exact test was conducted to verify the most enriched pathways, and the variation of each pathway in different stages was analyzed. SVM networks were trained and ROC curves were drawn based on the predicted results so as to evaluate the predictive effectiveness of the SVM model. Unsupervised hierarchical clustering analysis results showed that almost all the samples in stage III/IV were clustered together, while samples in stage I/II were clustered together. The correlation of feature genes in different stages was different. In addition, with the increase of malignant degree of lung cancer, the average shortest path of the network gradually increased, while the closeness centrality gradually decreased. Finally, four feature pathways that could distinguish different stages of LUAD were obtained and the ability was tested by the SVM model with an accuracy of 91%. Functional level differences were quantified based on the expression of feature genes in lung cancer patients of different stages, so as to help the diagnosis and prediction of lung cancer. The accuracy of our model in differentiating between stage I/II and stage III/IV could reach 91%.

USP53 promotes apoptosis and inhibits glycolysis in lung adenocarcinoma through FKBP51‐AKT1 signaling

Despite an overall decline in the incidence of new cases, lung adenocarcinoma continues to be a leading cause of cancer death worldwide. Due to lack of gene expression signatures for risk and prognosis stratification of lung adenocarcinoma, identifying novel molecular biomarkers and therapeutic targets may potentially improve lung adenocarcinoma prognosis and treatment. In the current study, we investigate the role of USP53 in lung adenocarcinoma. Bioinformatics analysis, quantitative reverse transcription polymerase chain reaction, and Western blot were employed to examine patterns of gene expression in human lung adenocarcinoma database, patient samples, and cancer cell lines. Stable cell lines were produced by transducing with USP53 overexpression vector or short hairpin RNA targeting USP53 in the presence and absence of AKT pathway inhibitor LY294002. Functional assays were carried out to examine the impact of USP53 and AKT pathway on lung adenocarcinoma cell viability, apoptosis, and glycolysis in vitro, as well as tumor growth in vivo. The correlation between USP53 and FKBP51 was measured by coimmunoprecipitation and ubiquitination assay. Decreased USP53 levels are a reliable marker of lung adenocarcinoma across published datasets, clinical samples, and cell culture lines. Low USP53 expression is linked to decreased apoptosis and increased metabolic activity, suggesting it acts as a tumor suppressor. USP53 regulates cell apoptosis and glycolysis through the AKT1 pathway. Mechanistically, USP53 deubiquitinates FKBP51, which in turn dephosphorylates AKT1, and ultimately inhibits tumor growth in lung adenocarcinoma. Taken together, our study establishes USP53 as a novel regulator of AKT1 pathway with an important role in tumorigenesis in lung adenocarcinoma.