Mesothelin Overexpression Is a Marker of Tumor Aggressiveness and Is Associated with Reduced Recurrence-Free and Overall Survival in Early-Stage Lung Adenocarcinoma

BackgroundSurvival after curative resection of early-stage lung adenocarcinoma (LUAD) varies and prognostic biomarkers are urgently needed.MethodsLarge-format tissue samples from a prospective cohort of 200 patients with resected LUAD were immunophenotyped for cancer hallmarks TP53, NF1, CD45, PD-1, PCNA, TUNEL, and FVIII, and were followed for median (95%CI)=2.34 (1.71–3.49) years.ResultsUnsupervised hierarchical clustering revealed two patient subgroups with similar clinicopathologic features and genotype, but with markedly different survival: “proliferative” patients (60%) with elevated TP53, NF1, CD45, and PCNA expression had 50% 5-year overall survival while “apoptotic” patients (40%) with high TUNEL had 70% 5-year survival [HR95%CI=2.23 (1.33–3.80); p=0.0069]. Cox regression and machine learning algorithms including random forests built clinically useful models: a score to predict overall survival and a formula and nomogram to predict tumour phenotype. The distinct LUAD phenotypes were validated in TCGA and KMplotter data and showed prognostic power supplementary to IASLC TNM stage and WHO histologic classification.ConclusionsTwo molecular subtypes of LUAD exist and their identification provides important prognostic information.

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Co-Expression of Coxsackievirus/Adenovirus Receptors and Desmoglein 2 in Lung Adenocarcinoma: A Comprehensive Analysis of Bioinformatics and Tissue Microarrays

Journal of Clinical Medicine ◽

10.3390/jcm9113693 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3693

Author(s):

Ching-Fu Weng ◽

Chi-Jung Huang ◽

Mei-Hsuan Wu ◽

Henry Hsin-Chung Lee ◽

Thai-Yen Ling

Keyword(s):

Overall Survival ◽

Survival Analysis ◽

Lung Adenocarcinoma ◽

Cox Regression ◽

Epithelial Mesenchymal Transition ◽

Early Stage ◽

The Cancer Genome Atlas ◽

Cancer Tissue ◽

Mesenchymal Transition ◽

Kaplan Meier

Introduction: Coxsackievirus/adenovirus receptors (CARs) and desmoglein-2 (DSG2) are similar molecules to adenovirus-based vectors in the cell membrane. They have been found to be associated with lung epithelial cell tumorigenesis and can be useful markers in predicting survival outcome in lung adenocarcinoma (LUAD). Methods: A gene ontology enrichment analysis disclosed that DSG2 was highly correlated with CAR. Survival analysis was then performed on 262 samples from the Cancer Genome Atlas, forming “Stage 1A” or “Stage 1B”. We therefore analyzed a tissue microarray (TMA) comprised of 108 lung samples and an immunohistochemical assay. Computer counting software was used to calculate the H-score of the immune intensity. Cox regression and Kaplan–Meier analyses were used to determine the prognostic value. Results: CAR and DSG2 genes are highly co-expressed in early stage LUAD and associated with significantly poorer survival (p = 0.0046). TMA also showed that CAR/DSG2 expressions were altered in lung cancer tissue. CAR in the TMA was correlated with proliferation, apoptosis, and epithelial–mesenchymal transition (EMT), while DSG2 was associated with proliferation only. The Kaplan–Meier survival analysis revealed that CAR, DSG2, or a co-expression of CAR/DSG2 was associated with poorer overall survival. Conclusions: The co-expression of CAR/DSG2 predicted a worse overall survival in LUAD. CAR combined with DSG2 expression can predict prognosis.

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Development and validation of a robust immune-related prognostic signature in early-stage lung adenocarcinoma

Journal of Translational Medicine ◽

10.1186/s12967-020-02545-z ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Pancheng Wu ◽

Yi Zheng ◽

Yanyu Wang ◽

Yadong Wang ◽

Naixin Liang

Keyword(s):

Overall Survival ◽

Lung Adenocarcinoma ◽

Early Stage ◽

Prognostic Signature ◽

Training Set ◽

Validation Data ◽

Data Set ◽

Screening Programs ◽

Immune Signature ◽

Immune Related Genes

Abstract Background The incidence of stage I and stage II lung adenocarcinoma (LUAD) is likely to increase with the introduction of annual screening programs for high-risk individuals. We aimed to identify a reliable prognostic signature with immune-related genes that can predict prognosis and help making individualized management for patients with early-stage LUAD. Methods The public LUAD cohorts were obtained from the large-scale databases including 4 microarray data sets from the Gene Expression Omnibus (GEO) and 1 RNA-seq data set from The Cancer Genome Atlas (TCGA) LUAD cohort. Only early-stage patients with clinical information were included. Cox proportional hazards regression model was performed to identify the candidate prognostic genes in GSE30219, GSE31210 and GSE50081 (training set). The prognostic signature was developed using the overlapped prognostic genes based on a risk score method. Kaplan–Meier curve with log-rank test and time-dependent receiver operating characteristic (ROC) curve were used to evaluate the prognostic value and performance of this signature, respectively. Furthermore, the robustness of this prognostic signature was further validated in TCGA-LUAD and GSE72094 cohorts. Results A prognostic immune signature consisting of 21 immune-related genes was constructed using the training set. The prognostic signature significantly stratified patients into high- and low-risk groups in terms of overall survival (OS) in training data set, including GSE30219 (HR = 4.31, 95% CI 2.29–8.11; P = 6.16E−06), GSE31210 (HR = 11.91, 95% CI 4.15–34.19; P = 4.10E−06), GSE50081 (HR = 3.63, 95% CI 1.90–6.95; P = 9.95E−05), the combined data set (HR = 3.15, 95% CI 1.98–5.02; P = 1.26E−06) and the validation data set, including TCGA-LUAD (HR = 2.16, 95% CI 1.49–3.13; P = 4.54E−05) and GSE72094 (HR = 2.95, 95% CI 1.86–4.70; P = 4.79E−06). Multivariate cox regression analysis demonstrated that the 21-gene signature could serve as an independent prognostic factor for OS after adjusting for other clinical factors. ROC curves revealed that the immune signature achieved good performance in predicting OS for early-stage LUAD. Several biological processes, including regulation of immune effector process, were enriched in the immune signature. Moreover, the combination of the signature with tumor stage showed more precise classification for prognosis prediction and treatment design. Conclusions Our study proposed a robust immune-related prognostic signature for estimating overall survival in early-stage LUAD, which may be contributed to make more accurate survival risk stratification and individualized clinical management for patients with early-stage LUAD.

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A Novel Risk-Score Model With Eight MiRNA Signatures for Overall Survival of Patients With Lung Adenocarcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.741112 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jun Wu ◽

Yuqing Lou ◽

Yi-Min Ma ◽

Jun Xu ◽

Tieliu Shi

Keyword(s):

Overall Survival ◽

Lung Adenocarcinoma ◽

Risk Score ◽

Early Stage ◽

Differential Expression Analysis ◽

The Cancer Genome Atlas ◽

Clinical Staging ◽

Risk Scores ◽

Regulatory Relationship ◽

Score Model

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer with heterogeneous outcomes and diverse therapeutic responses. To classify patients into different groups and facilitate the suitable therapeutic strategy, we first selected eight microRNA (miRNA) signatures in The Cancer Genome Atlas (TCGA)-LUAD cohort based on multi-strategy combination, including differential expression analysis, regulatory relationship, univariate survival analysis, importance clustering, and multivariate combinations analysis. Using the eight miRNA signatures, we further built novel risk scores based on the predefined cutoff and beta coefficients and divided the patients into high-risk and low-risk groups with significantly different overall survival time (p-value < 2 e−16). The risk-score model was confirmed with an independent dataset (p-value = 4.71 e−4). We also observed that the risk scores of early-stage patients were significantly lower than those of late-stage patients. Moreover, our model can also provide new insights into the current clinical staging system and can be regarded as an alternative system for patient stratification. This model unified the variable value as the beta coefficient facilitating the integration of biomarkers obtained from different omics data.

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Comprehensive Analysis of Clinical Significance, Immune Infiltration and Biological Role of m6A Regulators in Early-Stage Lung Adenocarcinoma

Frontiers in Immunology ◽

10.3389/fimmu.2021.698236 ◽

2021 ◽

Vol 12 ◽

Author(s):

Bolun Zhou ◽

Shugeng Gao

Keyword(s):

Overall Survival ◽

Lung Adenocarcinoma ◽

Early Stage ◽

Adoptive T Cell Therapy ◽

Predictive Score ◽

Poor Overall Survival ◽

T Cell Therapy ◽

Immune Infiltration ◽

Mutation Burden

Recent publications have revealed that N6-methyladenosine (m6A) modification is critically involved in tumorigenesis and metastasis. However, the correlation of m6A modification and immune infiltration in early-stage lung adenocarcinoma (LUAD) is still uncertain. We performed NMF clustering based on 23 m6A regulators and identify three distinct m6A clusters and three m6A related genes clusters (m6A cluster-R) in early-stage LUAD. The immune infiltrating levels were calculated using CIBERSORT, MCPcounter and ssGSEA algorithms. And we established the m6A-predictive score to quantify m6A modified phenotypes and predict immunotherapeutic responses. Based on the TME characteristics, different immune profiles were also identified among three m6A gene-related clusters. And the m6A-R-C2 was related to a favorable overall survival (OS), whereas m6A-R-C3 had unfavorable overall survival. The m6A-predictive score was built according to the expression levels of m6A-related genes, and patients could be stratified into subgroups with low/high scores. Patients with high scores had poor overall survival, enhanced immune infiltration, high tumor mutation burden and increased level of somatic mutation. Besides, patients with high scores had unfavorable overall survival in the anti-PD-1 cohort, whereas the overall survival of high-score patients was better in the adoptive T cell therapy cohort. Our work highlights that m6A modification is closely related to immune infiltration in early-stage LUAD, which also contributes to the development of more effective immunotherapy strategies.

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191: Heterogeneity among early-stage K-Ras driven lung adenocarcinoma predicts tumor aggressiveness and identifies Ddr1 as a therapeutic target

European Journal of Cancer ◽

10.1016/s0959-8049(14)50164-5 ◽

2014 ◽

Vol 50 ◽

pp. S43-S44

Author(s):

C. Ambrogio ◽

G. Gomez ◽

D. Santamaria ◽

M. Barbacid

Keyword(s):

Lung Adenocarcinoma ◽

Therapeutic Target ◽

Early Stage ◽

Tumor Aggressiveness

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Development and validation of a hypoxia-related gene signature to predict overall survival in early-stage lung adenocarcinoma patients

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920937904 ◽

2020 ◽

Vol 12 ◽

pp. 175883592093790

Author(s):

Jing Sun ◽

Tianyu Zhao ◽

Di Zhao ◽

Xin Qi ◽

Xuanwen Bao ◽

...

Keyword(s):

Overall Survival ◽

Risk Factor ◽

Decision Tree ◽

Risk Stratification ◽

Lung Adenocarcinoma ◽

Early Stage ◽

Staging System ◽

Gene Signature ◽

Significant Heterogeneity ◽

Related Gene

Background: Patients with early-stage lung adenocarcinoma (LUAD) exhibit significant heterogeneity in overall survival. The current tumour-node-metastasis staging system is insufficient to provide precise prediction for prognosis. Methods: We quantified the levels of various hallmarks of cancer and identified hypoxia as the primary risk factor for overall survival in early-stage LUAD. Different bioinformatic and statistical methods were combined to construct a robust hypoxia-related gene signature for prognosis. Furthermore, a decision tree and a nomogram were constructed based on the gene signature and clinicopathological features to improve risk stratification and quantify risk assessment for individual patients. Results: The hypoxia-related gene signature discriminated high-risk patients at an early stage in our investigated cohorts. Survival analyses demonstrated that our gene signature served as an independent risk factor for overall survival. The decision tree identified risk subgroups powerfully, and the nomogram exhibited high accuracy. Conclusions: Our study might contribute to the optimization of risk stratification for survival and personalized management of early-stage LUAD.

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Correlation of circulating miRNA levels with progression-free survival (PFS) and overall survival (OS) in early-stage lung adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.11099 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. 11099-11099 ◽

Cited By ~ 1

Author(s):

Francesco Grignani ◽

Riccardo Trombi ◽

Sara Baglivo ◽

Marco Gunnellini ◽

Marinella Di Carlo ◽

...

Keyword(s):

Overall Survival ◽

Lung Adenocarcinoma ◽

Early Stage ◽

Progression Free Survival ◽

Free Survival ◽

Circulating Mirna

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Improving Risk Stratification of Early Oral Tongue Cancer with TNM-Immune (TNM-I) Staging System

Cancers ◽

10.3390/cancers13133235 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3235

Author(s):

Alhadi Almangush ◽

Ibrahim O. Bello ◽

Ilkka Heikkinen ◽

Jaana Hagström ◽

Caj Haglund ◽

...

Keyword(s):

Overall Survival ◽

Tongue Cancer ◽

Early Stage ◽

Disease Free Survival ◽

Tumor Infiltrating Lymphocytes ◽

Staging System ◽

Oral Tongue ◽

Oral Tongue Cancer ◽

Important Player ◽

Infiltrating Lymphocytes

Although patients with early-stage oral tongue squamous cell carcinoma (OTSCC) show better survival than those with advanced disease, there is still a number of early-stage cases who will suffer from recurrence, cancer-related mortality and worse overall survival. Incorporation of an immune descriptive factor in the staging system can aid in improving risk assessment of early OTSCC. A total of 290 cases of early-stage OTSCC re-classified according to the American Joint Committee on Cancer (AJCC 8) staging were included in this study. Scores of tumor-infiltrating lymphocytes (TILs) were divided as low or high and incorporated in TNM AJCC 8 to form our proposed TNM-Immune system. Using AJCC 8, there were no significant differences in survival between T1 and T2 tumors (p > 0.05). Our proposed TNM-Immune staging system allowed for significant discrimination in risk between tumors of T1N0M0-Immune vs. T2N0M0-Immune. The latter associated with a worse overall survival with hazard ratio (HR) of 2.87 (95% CI 1.92–4.28; p < 0.001); HR of 2.41 (95% CI 1.26–4.60; p = 0.008) for disease-specific survival; and HR of 1.97 (95% CI 1.13–3.43; p = 0.017) for disease-free survival. The TNM-Immune staging system showed a powerful ability to identify cases with worse survival. The immune response is an important player which can be assessed by evaluating TILs, and it can be implemented in the staging criteria of early OTSCC. TNM-Immune staging forms a step towards a more personalized classification of early OTSCC.

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