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Development and validation of a gene-based classification model for pN2 lung adenocarcinoma

ABSTRACT: Lung adenocarcinoma (LUAD) with pathological ipsilateral mediastinal lymph node (LN) involvement (pN2) exhibits strong biological and clinical heterogeneity. Thus, it is necessary to classify the biomolecular characteristics that lead to the prognostic heterogeneity of pN2-LUAD. The clinical characteristics and bulk RNA sequencing (RNA-seq) data of 75 patients with pN2-LUAD obtained from The Cancer Genome Atlas (TCGA) database were collected as the training set. The disease-free survival (DFS) and overall survival (OS) of patients with different molecular classifications were evaluated. Next, differentially expressed genes (DEGs), biology, and immune cell infiltration in the microenvironment were analysed. Finally, DEGs in the pN2-A and pN2-B groups were included using a least absolute shrinkage and selection operator (LASSO) model, and gene signatures were selected for pN2-A/B type classification. The RNA-seq and single-nucleus RNA sequencing (snRNA-seq) data from our center (n=58) and the GSE68465 dataset (n=53) were used as the validation data sets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282774 | GEO | 2024/11/26

REPOSITORIES: GEO

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Project description:Abstract: Immunotherapy has emerged as a crucial treatment approach for lung adenocarcinoma (LUAD), yet a notable percentage of patients do not exhibit the anticipated prognosis and therapeutic response. In this study, we embarked on a comprehensive analysis of immune infiltration-related genes in LUAD by integrating transcriptome sequencing data and TCGA dataset. And an immune risk prognosis model was developed, which accurately forecasts the prognosis and predicts the immunotherapy efficacy in LUAD. Patients with LUAD were categorized into high-risk and low-risk groups based on the model's risk value. The high-risk group exhibited a poorer prognosis, higher tumor mutation burden (TMB), greater genomic heterogeneity and lower immune scores. In contrast, the low-risk group manifested characteristics conducive to immunotherapy, including a more favorable prognosis, heightened sensitivity to immunotherapy and reduced likelihood of immune escape. The robustness of the model's predictive capability was corroborated using the GEO dataset, Nomogram and an independent immunotherapy cohort. Furthermore, the model risk value was found to be significantly associated with the prognosis of LUAD patients, genomic heterogeneity, immune cell infiltration, immune regulation and immunotherapy outcomes. Additionally, we characterized the significance of the model's feature factors using single-cell clustering and pseudo-temporal analysis, revealing that the model's feature genes are predominantly located in tumor-infiltrating T cells, particularly in the exhausted and effector subtypes. TNFRSF11A emerged as a key gene in the model, promoting LUAD cell proliferation, migration, and apoptosis, and involvement in LUAD M6A methylation and PD-L1-mediated immune escape. TNFRSF11A was mainly expressed in T cell clusters and represented a potential immune system regulatory factor associated with T cell exhaustion, fostering malignant progression in LUAD cells. Our study offers new mechanistic insights and therapeutic targets for the biological behaviors and immune suppression in LUAD.

Project description:Accumulating evidence indicates that RNA-binding proteins (RBPs) are involved in tumorigenesis. As a member of DEAD-box RBPs, DDX17 has a significant role in various contexts, such as mRNA translation, pre-mRNA splicing, ribosome biogenesis, and DNA repair. However, whether DDX17 is involved in the regulation of gene expression and alternative splicing in lung adenocarcinoma (LUAD) remains unclear. Methods: CCK-8 assay was used to evaluate cells proliferation. Cell apoptosis was evaluated by an Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) apoptosis detection kit. We used high-throughput RNA sequencing (RNA-seq) to determine differentially expressed genes (DEGs) and alternative splicing (AS) events in DDX17 knockdown LUAD cells. Functional and pathway enrichment analysis was also performed. Results: Knockdown of DDX17 by siRNA significantly inhibited the proliferation and induced apoptosis in A549 cells. 5243 DEGs were identified. Functional enrichment analyses indicated that these genes were mainly enriched in biological processes including regulation of transcription, regulation of cell growth, DNA repair. DDX17 knockdown increased the level of pro-apoptotic gene expression and decreased the expression of pro-proliferation genes. We also showed that DDX17-regulated AS events revealed by computational analysis using ABLas software in A549 cells were highly validated by RT-qPCR, and also validated by TCGA-LUAD dataset. Functional enrichment analyses showed regulated alternatively spliced genes (RASGs) were mainly enriched in biological processes related to apoptotic process, DNA repair, positive regulation of translation, positive regulation of apoptotic process. Conclusion: The present findings suggest that DDX17 may function as an oncogene by regulating both the expression and the alternative splicing of genes associated with proliferation, invasion and apoptosis in LUAD cells. Our findings may bring new insights into understanding the molecular mechanisms of LUAD and provide a new direction for LUAD treatment.

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Development and validation of a gene-based classification model for pN2 lung adenocarcinoma

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