Translating Gene Signatures Into a Pathologic Feature: Tumor Necrosis Predicts Disease Relapse in Operable and Stage I Lung Adenocarcinoma

2018 ◽  
pp. 1-13
Author(s):  
Emily Pei-Ying Lin ◽  
Tzu-Hung Hsiao ◽  
Jo-yang Lu ◽  
Siao-Han Wong ◽  
Tzu-Pin Lu ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Lung Adenocarcinoma ◽  
Tumor Necrosis ◽  
Lung Squamous Cell Carcinoma ◽  
Stage I ◽  
The Cancer Genome Atlas ◽  
Pathologic Feature ◽  
Gene Signatures ◽  
Cancer Genome Atlas ◽  
Lung Adenocarcinomas

Purpose The high 5-year disease relapse rate in patients with stage I lung adenocarcinoma indicates the need for additional risk stratification parameters. This study assessed whether gene signatures translate into a pathologic feature for better disease stratification. Materials and Methods The mutual interdependence and risk stratification power of three gene signatures, cell cycle, hypoxia, and mammalian target of rapamycin (mTOR), were investigated in nine cohorts of patients with lung adenocarcinoma and five cohorts of patients with lung squamous cell carcinoma. The translation from gene signatures to a pathologic feature, tumor necrosis, was validated in The Cancer Genome Atlas lung adenocarcinoma cohort. The translation of signature score to pathway activity was further investigated by integrative analyses using The Cancer Genome Atlas and The Cancer Protein Atlas lung adenocarcinoma data sets. Results The results showed that the three gene signatures were mutually interdependent in lung adenocarcinoma but not in lung squamous cell carcinoma. The signature activities were higher in necrosis-positive tumors than in necrosis-negative tumors. The signature score correlated with the expression level of the representative protein that implicated the activity of each pathway. These signatures stratified patients with operable and stage I lung adenocarcinomas into different risk groups independent of age and stage. Furthermore, the signatures translated to a pathologic feature, tumor necrosis, which predicted shorter overall and relapse-free survival in patients with operable and stage I lung adenocarcinomas. Conclusion This study showed that gene signatures could translate into a pathologic feature, tumor necrosis, with risk stratification ability in patients with operable and stage I lung adenocarcinomas.

scholarly journals High KRT8 Expression Independently Predicts Poor Prognosis for Lung Adenocarcinoma Patients

Genes ◽  
2019 ◽  
Vol 10 (1) ◽  
pp. 36 ◽  
Author(s):  
Longxiang Xie ◽  
Yifang Dang ◽  
Jinshuai Guo ◽  
Xiaoxiao Sun ◽  
Tiantian Xie ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Mrna Expression ◽  
Prognostic Significance ◽  
Lung Squamous Cell Carcinoma ◽  
Prognostic Indicator ◽  
The Cancer Genome Atlas ◽  
Normal Lung ◽  
Rna Seq ◽  
Cancer Genome Atlas ◽  
Dna Copy Number Alterations

Keratin 8 (KRT8), a type II basic intermediate filament (IF) protein, is essential for the development and metastasis of various cancers. In this study, by analyzing RNA-seq data from the Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), we have determined the expression profile of KRT8, and assessed its prognostic significance and the possible mechanism underlying the dysregulation. Our results showed that KRT8 mRNA expression was significantly up-regulated in both LUAD and LUSC tissues compared with normal lung tissues. The high KRT8 expression group for LUAD patients significantly reduced overall survival (OS) and recurrence-free survival (RFS). Univariate and multivariate analysis revealed that KRT8 expression was an independent prognostic indicator for poor OS and RFS in LUAD patients. However, KRT8 expression had no prognostic value in terms of OS and RFS for LUSC. By exploring DNA copy number alterations (CNAs) of the KRT8 gene in LUAD, we found that DNA low copy gain (+1 and +2) was associated with elevated KRT8 mRNA expression. From the above findings, we have deduced that KRT8 is aberrantly expressed in LUAD tissues and that its expression might independently predict poor OS and RFS for LUAD patients, but not for LUSC patients.

scholarly journals UBE2D1 RNA Expression Was an Independent Unfavorable Prognostic Indicator in Lung Adenocarcinoma, but Not in Lung Squamous Cell Carcinoma

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Liyan Hou ◽  
Yingbo Li ◽  
Ying Wang ◽  
Dongqiang Xu ◽  
Hailing Cui ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Squamous Cell Carcinoma ◽  
Lung Adenocarcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Survival Data ◽  
Lung Squamous Cell Carcinoma ◽  
Prognostic Indicator ◽  
The Cancer Genome Atlas ◽  
Rna Expression

In this study, we investigated the potential prognostic value of ubiquitin-conjugating enzyme E2D1 (UBE2D1) RNA expression in different histological subtypes of non-small-cell lung cancer (NSCLC). A retrospective study was performed by using molecular, clinicopathological, and survival data in the Cancer Genome Atlas (TCGA)—Lung Cancer. Results showed that both lung adenocarcinoma (LUAD) (N=514) and lung squamous cell carcinoma (LUSC) (N=502) tissues had significantly elevated UBE2D1 RNA expression compared to the normal tissues (p<0.001 and p=0.036, respectively). UBE2D1 RNA expression was significantly higher in LUAD than in LUSC tissues. Increased UBE2D1 RNA expression was independently associated with shorter OS (HR: 1.359, 95% CI: 1.031–1.791, p=0.029) and RFS (HR: 1.842, 95% CI: 1.353–2.508, p<0.001) in LUAD patients, but not in LUSC patients. DNA amplification was common in LUAD patients (88/551, 16.0%) and was associated with significantly upregulated UBE2D1 RNA expression. Based on these findings, we infer that UBE2D1 RNA expression might only serve as an independent prognostic indicator of unfavorable OS and RFS in LUAD, but not in LUSC.

scholarly journals Role of INSL4 Signaling in Sustaining the Growth and Viability of LKB1-Inactivated Lung Cancer

2018 ◽  
Vol 111 (7) ◽  
pp. 664-674 ◽  
Author(s):  
Rongqiang Yang ◽  
Steven W Li ◽  
Zirong Chen ◽  
Xin Zhou ◽  
Wei Ni ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transcriptome Profiling ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Growth And Survival ◽  
Cancer Genome Atlas ◽  
Lung Adenocarcinomas ◽  
Genome Atlas

Abstract Background The LKB1 tumor suppressor gene is commonly inactivated in non-small cell lung carcinomas (NSCLC), a major form of lung cancer. Targeted therapies for LKB1-inactivated lung cancer are currently unavailable. Identification of critical signaling components downstream of LKB1 inactivation has the potential to uncover rational therapeutic targets. Here we investigated the role of INSL4, a member of the insulin/IGF/relaxin superfamily, in LKB1-inactivated NSCLCs. Methods INSL4 expression was analyzed using global transcriptome profiling, quantitative reverse transcription PCR, western blotting, enzyme-linked immunosorbent assay, and RNA in situ hybridization in human NSCLC cell lines and tumor specimens. INSL4 gene expression and clinical data from The Cancer Genome Atlas lung adenocarcinomas (n = 515) were analyzed using log-rank and Fisher exact tests. INSL4 functions were studied using short hairpin RNA (shRNA) knockdown, overexpression, transcriptome profiling, cell growth, and survival assays in vitro and in vivo. All statistical tests were two-sided. Results INSL4 was identified as a novel downstream target of LKB1 deficiency and its expression was induced through aberrant CRTC-CREB activation. INSL4 was highly induced in LKB1-deficient NSCLC cells (up to 543-fold) and 9 of 41 primary tumors, although undetectable in all normal tissues except the placenta. Lung adenocarcinomas from The Cancer Genome Atlas with high and low INSL4 expression (with the top 10th percentile as cutoff) showed statistically significant differences for advanced tumor stage (P < .001), lymph node metastasis (P = .001), and tumor size (P = .01). The INSL4-high group showed worse survival than the INSL4-low group (P < .001). Sustained INSL4 expression was required for the growth and viability of LKB1-inactivated NSCLC cells in vitro and in a mouse xenograft model (n = 5 mice per group). Expression profiling revealed INSL4 as a critical regulator of cell cycle, growth, and survival. Conclusions LKB1 deficiency induces an autocrine INSL4 signaling that critically supports the growth and survival of lung cancer cells. Therefore, aberrant INSL4 signaling is a promising therapeutic target for LKB1-deficient lung cancers.

scholarly journals Increased GOLM1 Expression Independently Predicts Unfavorable Overall Survival and Recurrence-Free Survival in Lung Adenocarcinoma

2018 ◽  
Vol 25 (1) ◽  
pp. 107327481877800 ◽  
Author(s):  
Xi Liu ◽  
Lei Chen ◽  
Tao Zhang
Keyword(s):  
Overall Survival ◽  
Lung Adenocarcinoma ◽  
Survival Data ◽  
Methylation Status ◽  
Lung Squamous Cell Carcinoma ◽  
Prognostic Indicator ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Recurrence Free Survival ◽  
Free Survival

Golgi membrane protein 1 (GOLM1) is a transmembrane glycoprotein of the Golgi cisternae, which is implicated in carcinogenesis of multiple types of cancer. In this study, using data from the Gene Expression Omnibus and The Cancer Genome Atlas, we compared the expression of GOLM1 in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) and studied its prognostic value in terms of overall survival (OS) and recurrence-free survival (RFS) in these 2 subtypes of non-small cell lung cancer (NSCLC). Results showed that GOLM1 was significantly upregulated in both LUAD and LUSC tissues compared to the normal controls. However, GOLM1 expression was higher in LUAD tissues than in LUSC tissues. More importantly, using over 10 years’ survival data from 502 patients with LUAD and 494 patients with LUSC, we found that high GOLM1 expression was associated with unfavorable OS and RFS in patients with LUAD, but not in patients with LUSC. The following univariate and multivariate analyses confirmed that increased GOLM1 expression was an independent prognostic indicator of poor OS (hazard ratio [HR]: 1.30, 95% confidence interval [CI]: 1.11-1.54, P = .002) and RFS (HR: 1.37, 95% CI: 1.14-1.64, P = .001) in patients with LUAD. Of 511 cases with LUAD, 248 (48.5%) had heterozygous loss (−1), while 28 (5.5%) of 511 cases with LUAD had low-level copy gain (+1). In addition, we also found that the methylation status of 1 CpG site (chr9: 88,694,942-88,694,944) showed a weak negative correlation with GOLM1 expression (Pearson r = −0.25). Based on these findings, we infer that GOLM1 might serve as a valuable prognostic biomarker in LUAD, but not in LUSC. In addition, DNA copy number alterations and methylation might be 2 important mechanisms of dysregulated GOLM1 in LUAD.

Identification of predictive biomarker for immunotherapy by associating with CD8+T cell Infiltration in lung adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21177-e21177
Author(s):  
Puyuan Xing ◽  
Teng Li ◽  
Han Wang ◽  
Lin Yang ◽  
Guoqiang Wang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Predictive Performance ◽  
Predictive Biomarker ◽  
Pooled Analysis ◽  
The Cancer Genome Atlas ◽  
T Cell Infiltration ◽  
Or Groups ◽  
Cancer Genome Atlas

e21177 Background: Tumor immune microenvironment (TIME) has been proved associated with response to immunotherapy(I/O). We hypothesized that screening potential mutation pattern which could significantly impact the tumor infiltrating lymphocytes(TILs) can help us to identify predictive biomarkers for I/O in Lung adenocarcinoma(LUAD). Methods: Multiple-dimensional data from The Cancer Genome Atlas LUAD cohort (n = 514) was used for building a mathematical model beween mutation signature and CD8+TIL score (based on MCP-counter). An independent public validation cohort (cohort 1: LUAD, n = 598) were used to assess the immunotherapeutic predictive performance of the potential mutation patterns. Results: Top 100 gene associated with CD8+TIL score were selected based on MC+ model which can provides the minimum non-convexity of the penalized loss given the level of bias. Seven TIME genes (SPTA1 coef 0.09; MET coef 0.02; HSD3B1 coef -0.00; STAT4 coef -0.01; EGFR coef -0.08; PIK3CB coef -0.08; KEAP1 coef -0.24) were generated by taking the intersection of the top 100 mutant genes and FoundationOne (F1) CDx NGS 315 genes panel and verified in cohort 1. Survival analysis showed that SPTA1mt was the only one that associated with both significantly longer PFS (median PFS 3.15 vs 2.89 months; HR 0.65; 95% CI 0.45 to 0.93; p = 0.02) and OS (median PFS 15.08 vs 7.36 months; HR 0.59; 95% CI 0.40 to 0.88; p = 0.01) for patients who received I/O compared with chemotherapy(CT) among seven TIME genes. In order to test our hypothesis fully, a pooled analysis of SPTA1mt (a core positive predictors of CD8+TILs) and KEAP1mt (a core negative predictors for CD8+TILs ) were conducted and yielded that co occurrence of SPTA1mt and KEAP1mt had a compound effects for TIME. The validation showed that co mutation with SPTA1mt was accompanied by an decrease HR for I/O vs. CT in both PFS (HR S+K vs. K only 0.59 vs 1.56) and OS (HR S+K vs. K only 0.39 vs 0.80) for KEAP1mt patients. Conclusions: Our data show that it is feasible to identify individuals or groups of individual with specific mutations to immunotherapy responses from TIME view. SPTA1mt was a core predictors for higher CD8+ TILs and can be identified as a predictive biomarker for benefit from I/O compared with CT. Prospective studies are warranted for further investigation.

scholarly journals Deciphering N6-Methyladenosine-Related Genes Signature to Predict Survival in Lung Adenocarcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Jie Zhu ◽  
Min Wang ◽  
Daixing Hu
Keyword(s):  
Lung Adenocarcinoma ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Consensus Clustering ◽  
Lasso Regression ◽  
Gene Expressions ◽  
Tumor Tissues ◽  
Cancer Genome Atlas ◽  
Selection Operator ◽  
Cox Analysis

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death. Among these, lung adenocarcinoma (LUAD) accounts for most cases. Due to the improvement of precision medicine based on molecular characterization, the treatment of LUAD underwent significant changes. With these changes, the prognosis of LUAD becomes diverse. N6-methyladenosine (m6A) is the most predominant modification in mRNAs, which has been a research hotspot in the field of oncology. Nevertheless, little has been studied to reveal the correlations between the m6A-related genes and prognosis in LUAD. Thus, we conducted a comprehensive analysis of m6A-related gene expressions in LUAD patients based on The Cancer Genome Atlas (TCGA) database by revealing their relationship with prognosis. Different expressions of the m6A-related genes in tumor tissues and non-tumor tissues were confirmed. Furthermore, their relationship with prognosis was studied via Consensus Clustering Analysis, Principal Components Analysis (PCA), and Least Absolute Shrinkage and Selection Operator (LASSO) Regression. Based on the above analyses, a m6A-based signature to predict the overall survival (OS) in LUAD was successfully established. Among the 479 cases, we found that most of the m6A-related genes were differentially expressed between tumor and non-tumor tissues. Six genes, HNRNPC, METTL3, YTHDC2, KIAA1429, ALKBH5, and YTHDF1 were screened to build a risk scoring signature, which is strongly related to the clinical features pathological stages (p<0.05), M stages (p<0.05), T stages (p < 0.05), gender (p=0.04), and survival outcome (p=0.02). Multivariate Cox analysis indicated that risk value could be used as an independent prognostic factor, revealing that the m6A-related genes signature has great predictive value. Its efficacy was also validated by data from the Gene Expression Omnibus (GEO) database.

scholarly journals ITGB1-DT/ARNTL2 axis may be a novel biomarker in lung adenocarcinoma: a bioinformatics analysis and experimental validation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Bai-Quan Qiu ◽  
Xia-Hui Lin ◽  
Song-Qing Lai ◽  
Feng Lu ◽  
Kun Lin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Cox Regression ◽  
Malignant Tumors ◽  
Expression Profiles ◽  
The Cancer Genome Atlas ◽  
Hub Genes ◽  
Immune Infiltration ◽  
Prognostic Effect ◽  
Cancer Genome Atlas

Abstract Background Lung cancer is one of the most lethal malignant tumors that endangers human health. Lung adenocarcinoma (LUAD) has increased dramatically in recent decades, accounting for nearly 40% of all lung cancer cases. Increasing evidence points to the importance of the competitive endogenous RNA (ceRNA) intrinsic mechanism in various human cancers. However, behavioral characteristics of the ceRNA network in lung adenocarcinoma need further study. Methods Groups based on SLC2A1 expression were used in this study to identify associated ceRNA networks and potential prognostic markers in lung adenocarcinoma. The Cancer Genome Atlas (TCGA) database was used to obtain the patients' lncRNA, miRNA, and mRNA expression profiles, as well as clinical data. Informatics techniques were used to investigate the effect of hub genes on prognosis. The Cox regression analyses were performed to evaluate the prognostic effect of hub genes. The methylation, GSEA, and immune infiltration analyses were utilized to explore the potential mechanisms of the hub gene. The CCK-8, transwell, and colony formation assays were performed to detect the proliferation and invasion of lung cancer cells. Results We eventually identified the ITGB1-DT/ARNTL2 axis as an independent fact may promote lung adenocarcinoma progression. Furthermore, methylation analysis revealed that hypo-methylation may cause the dysregulated ITGB1-DT/ARNTL2 axis, and immune infiltration analysis revealed that the ITGB1-DT/ARNTL2 axis may affect the immune microenvironment and the progression of lung adenocarcinoma. The CCK-8, transwell, and colonu formation assays suggested that ITGB1-DT/ARNTL2 promotes the progression of lung adenocarcinoma. And hsa-miR-30b-3p reversed the ITGB1/ARNTL2-mediated oncogenic processes. Conclusion Our study identified the ITGB1-DT/ARNTL2 axis as a novel prognostic biomarker affects the prognosis of lung adenocarcinoma.

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