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A novel diagnostic system to evaluate epidermal growth factor receptor impact as a prognostic and therapeutic indicator for lung adenocarcinoma.

ABSTRACT: Many driver pathways for cancer cell proliferation have been reported. Driver pathway activation is often evaluated based on a single hotspot mutation such as EGFR L858R. However, because of complex intratumoral networks, the impact of a driver pathway cannot be predicted based on only a single gene mutation. Here, we developed a novel diagnostic system named the "EGFR impact score" which is based on multiplex mRNA expression profiles, which can predict the impact of the EGFR pathway in lung cancer cells and the effect of EGFR-tyrosine kinase inhibitors on malignancy. The EGFR impact score indicated robust predictive power for the prognosis of early-stage lung cancer because this score can evaluate the impact of the EGFR pathway on the tumor and genomic instability. Additionally, the molecular features of the poor prognostic group resembled those of biomarkers associated with immune checkpoint inhibitors. The EGFR impact score is a novel prognostic and therapeutic indicator for lung adenocarcinoma.

SUBMITTER: Takakuwa K

PROVIDER: S-EPMC7148318 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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A novel diagnostic system to evaluate epidermal growth factor receptor impact as a prognostic and therapeutic indicator for lung adenocarcinoma.

Takakuwa Kazuya K Mogushi Kaoru K Han Min M Fujii Tomoaki T Hosoya Masaki M Yamanami Arina A Akita Tomomi T Yamashita Chikamasa C Hayashida Tetsu T Kato Shunsuke S Yamaguchi Shigeo S

Scientific reports 20200410 1

Many driver pathways for cancer cell proliferation have been reported. Driver pathway activation is often evaluated based on a single hotspot mutation such as EGFR L858R. However, because of complex intratumoral networks, the impact of a driver pathway cannot be predicted based on only a single gene mutation. Here, we developed a novel diagnostic system named the "EGFR impact score" which is based on multiplex mRNA expression profiles, which can predict the impact of the EGFR pathway in lung can ...[more]

PMID: 32277151

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Project description:BackgroundThe nuclear translocation of epidermal growth factor receptor (EGFR) has been considered to play a role in carcinogenesis. However, the relevance of differentially located EGFR proteins in lung cancer remains unclear.MethodsWe examined 161 patients with primary lung adenocarcinoma to detect EGFR expression in lung cancer cells using immunohistochemistry and determined the correlations of EGFR expression with clinical characteristics, EGFR mutations, and survival time. Moreover, we graded complete membranous staining with strong intensity as high membranous EGFR (mEGFR) expression, and nuclear EGFR staining with strong intensity as high nuclear (nEGFR) expression.ResultsThe prevalence of high mEGFR and nEGFR expression in lung adenocarcinoma was 42.86 and 39.13%, respectively. After multivariate analyses, high mEGFR expression was associated with a significantly reduced mortality risk in older patients, those with a history of smoking, and those without brain metastasis (hazard ratio[95% confidential interval], HR[95% CI] = 0.55[0.32~ 0.92]; 0.51[0.26~ 0.98] and 0.56[0.33~ 0.94], in overall survival, respectively). An association between high nEGFR expression and early recurrence was observed in patients with metastasis (HR[95% CI] =1.68[1.05~ 2.68], in progression-free survival). Notably, patients with low mEGFR and low nEGFR expression had the lowest survival rate in cases without brain metastasis (p = 0.018) and with a history of smoking (p = 0.062) and total EGFR (any high mEGFR or nEGFR) expression indicated a more favorable response to platinum-based chemotherapy regardless of EGFR mutations (HR[95% CI] =0.33[0.12-0.92]; adjusted HR[95% CI] = 0.36[0.13~ 1.02] with the use of tyrosine kinase inhibitor).ConclusionsEGFR proteins at different cellular locations in lung adenocarcinoma might influence the biology of cancer cells and are an independent indicator of more favorable prognosis and treatment response.

Project description:BackgroundLung cancer has the highest death rate among cancers globally. Accumulating evidence has indicated that cancer-related inflammation plays an important role in the initiation and progression of lung cancer. However, the prognosis, immunological role, and associated regulation axis of inflammatory response-related gene (IRRGs) in non-small-cell lung cancer (NSCLC) remains unclear.MethodsIn this study, we perform comprehensive bioinformatics analysis and constructed a prognostic inflammatory response-related gene (IRRGs) and related competing endogenous RNA (ceRNA) network. We also utilized the Pearson's correlation analysis to determine the correlation between IRRGs expression and tumor mutational burden (TMB), microsatellite instability (MSI), tumor-immune infiltration, and the drug sensitivity in NSCLC. Growth curve and Transwell assay used to verify the function of SNHG17 on NSCLC progression.ResultsFirst, we found that IRRGs were significantly upregulated in lung cancer, and its high expression was correlated with poor prognosis; high expression of IRRGs was significantly correlated with the tumor stage and poor prognosis in lung cancer patients. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment indicated that these IRRGs are mainly involved in the inflammatory and immune response-related signaling pathway in the progression of NSCLC. We utilized 10 prognostic-related genes to construct a prognostic IRRGs model that could predict the overall survival of lung adenocarcinoma (LUAD) patients possessing high specificity and accuracy. Our evidence demonstrated that IRRGs expression was significantly correlated with the TMB, MSI, immune-cell infiltration, and diverse cancer-related drug sensitivity. Finally, we identified the upstream regulatory axis of IRRGs in NSCLC, namely, lncRNA MIR503HG/SNHG17/miR-330-3p/regulatory axis. Finally, knockdown of SNHG17 expression inhibited lung adenocarcinoma (LUAD) cell proliferation and migration. Our findings confirmed that SNHG17 is a novel oncogenic lncRNA and may be a biomarker for the prognosis and diagnosis of LUAD.ConclusionDNA hypomethylation/lncRNA MIR503HG/SNHG17/microRNA-330-3p/regulatory axis may be a valuable biomarker for prognosis and is significantly correlated with immune cell infiltration in lung cancer.

Project description:Lung adenocarcinoma (LUAD) has been the major cause of tumor-associated mortality in recent years and exhibits a poor outcome. New data revealed that peroxisomes have a function in the regulation of the development and progression of several tumors. However, the prognostic values of peroxisome-related genes (PRGs) were rarely reported. Genomic sequence, mutation, and clinical data of 535 LUAD tissues were obtained from TCGA data sets. Within the TCGA cohort, a multigene signature was constructed with the assistance of the LASSO Cox regression model. Three GEO data sets, including GSE3141, GSE31210, and GSE72094, were obtained as validation cohorts. ROC assays, Kaplan-Meier methods, and multivariate assays were applied to examine the prognostic capacities of the novel signature. Gene Set Enrichment Analysis (GSEA) was performed to further understand the underlying molecular mechanisms. In this study, we identified 47 differentially expressed peroxisome-related genes (PRGs), including 25 increased and 22 decreased PRGs. A prognostic model of six PRGs was established. The univariate and multivariate Cox analyses both showed that the p value of risk score was less than 0.05. In LUAD patients, the strong connection between the risk score and overall survival was further verified in three other GEO data sets. TMB and cancer stem cell infiltration were shown to be significantly higher in the high-risk group in comparison to the low-risk group. The TIDE score of the group with the low risk was considerably greater than that of the group with the high risk. Several drugs, targeting PRG-related genes, were available for the treatments of LUAD. Overall, we developed a novel peroxisome-related prognostic signature for LUAD patients. This signature could successfully indicate LUAD patients' chances of survival as well as their immune system's responsiveness to treatments. In addition, it has the potential to serve as immunotherapeutic targets for LUAD patients.

Project description:BackgroundThe interactions between tumor cells and the host immune system play a crucial role in lung cancer progression and resistance to treatment. The alterations of EGFR signaling have the potential to produce an ineffective tumor-associated immune microenvironment by upregulating a series of immune suppressors, including inhibitory immune checkpoints, immunosuppressive cells, and cytokines. Elevated Heparin-binding EGF-like growth factor (HB-EGF) expression, one EGFR ligand correlated with higher histology grading, worse patient prognosis, and lower overall survival rate, acts as a chemotactic factor. However, the role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in the accumulation of immune cells in the tumor microenvironment remains unclear.MethodsThe clinical association of HB-EGF expression in lung cancer was examined using the Gene Expression Omnibus (GEO) repository. HB-EGF expression in different cell types was determined using single-cell RNA sequencing (scRNA-seq) dataset. The correlation between HB-EGF expression and cancer-immune infiltrated cells was investigated by performing TIMER and ClueGo pathways analysis from TCGA database. The chemotaxis of HB-EGF and macrophage infiltration was investigated using migration and immunohistochemical staining.ResultsThe high HB-EGF expression was significantly correlated with poor overall survival in patients with lung adenocarcinoma (LUAD) but not lung squamous cell carcinoma (LUSC). Moreover, HB-EGF expression was correlated with the infiltration of monocytes, macrophages, neutrophils, and dendritic cells in LUAD but not in LUSC. Analysis of scRNA-seq data revealed high HB-EGF expression in lung cancer cells and myeloid cells. Results from the pathway analysis and cell-based experiment indicated that elevated HB-EGF expression was associated with the presence of macrophage and lung cancer cell migration. HB-EGF was highly expressed in tumors and correlated with M2 macrophage infiltration in LUAD.ConclusionsHB-EGF is a potential prognostic marker and therapeutic target for lung cancer progression, particularly in LUAD.

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A novel diagnostic system to evaluate epidermal growth factor receptor impact as a prognostic and therapeutic indicator for lung adenocarcinoma.

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A novel diagnostic system to evaluate epidermal growth factor receptor impact as a prognostic and therapeutic indicator for lung adenocarcinoma.

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