Integrative Molecular Analyses of an Individual Transcription Factor-Based Genomic Model for Lung Cancer Prognosis

Yao, Rong; Zhou, Leilei; Guo, Zhaojiang; Zhang, Dahong; Zhang, Tiecheng

doi:10.1155/2021/5125643

Cited by 3 publications

(3 citation statements)

References 37 publications

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“…NPAS2 was identified as an oncogene in hepatocellular carcinoma and was related to infiltration of immune cells [ 23 ]. In accordance with our findings, increased expression of NPAS2 has been suggested to indicate poor survival in lung cancer [ 24 , 25 ]. NPAS2 was overexpressed in anaplastic thyroid carcinoma and facilitated malignant progression [ 26 ].…”

Section: Discussionsupporting

confidence: 92%

Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma

et al. 2023

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Background Chromatin regulators (CRs) are critical epigenetic modifiers and have been reported to play critical roles during the progression of various tumors, but their role in lung adenocarcinoma (LUAD) has not been comprehensively studied. Methods Differential expression and univariate Cox regression analyses were conducted to identify the prognostic CRs. Consensus clustering was applied to classify the subtypes of LUAD based on prognostic CRs. LASSO-multivariate Cox regression method was used for construction of a prognostic signature and development of chromatin regulator-related gene index (CRGI). The capacity of CRGI to distinguish survival was evaluated via Kaplan–Meier method in multiple datasets. Relationship between CRGI and tumor microenvironment (TME) was evaluated. Additionally, clinical variables and CRGI were incorporated to create a nomogram. The role of the prognostic gene NPAS2 in LUAD was elucidated via clinical samples validation and a series of in vitro and in vivo experiments. Results Two subtypes of LUAD were classified based on 46 prognostic CRs via consensus clustering which had significantly different survival and TME. A prognostic signature consisting of six CRs (MOCS, PBK, CBX3, A1CF, NPAS2, and CTCFL) was developed and proved to be an effective survival predictor in multiple independent datasets. The prognostic signature was also demonstrated to be an indicator of TME and sensitivity to immunotherapy and chemotherapy. The nomogram was suggested to be a simple tool that can predict survival accurately. Clinical samples show that NPAS2 is highly expressed in LUAD tissues, and in vitro and in vivo experiments demonstrated that inhibition of NPAS2 impeded malignant progression of LUAD cells. Conclusions Our study comprehensively unveiled the functions of CRs in LUAD, developed a classifier to predict survival and response to treatments, and suggested that NPAS2 promoted LUAD progression for the first time.

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Section: Discussionsupporting

confidence: 92%

Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma

et al. 2023

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“…Further examples included SIX1 66 and TFAP2D 67 , along with their regulatees, demonstrating the diverse array of biomolecules identified by the Taiji analysis that were implicated in NSCLC development and progression ( Figure S6 and S7).…”

Section: Resultsmentioning

confidence: 99%

Comprehensive multimodal and multiomic profiling reveals epigenetic and transcriptional reprogramming in lung tumors

Wu,

Liu,

Zheng

et al. 2024

Preprint

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Epigenomic mechanisms are critically involved in mediation of genetic and environmental factors that underlie cancer development. Histone modifications represent highly informative epigenomic marks that reveal activation and repression of gene activities and dysregulation of transcriptional control due to tumorigenesis. Here, we present a comprehensive epigenomic and transcriptomic mapping of 18 tumor and 20 non-neoplastic tissues from non-small cell lung adenocarcinoma patients. Our profiling covers 5 histone marks including activating (H3K4me3, H3K4me1, and H3K27ac) and repressive (H3K27me3 and H3K9me3) marks and the transcriptome using only 20 mg of tissue per sample, enabled by low-input omic technologies. Using advanced integrative bioinformatic analysis, we uncovered cancer-driving signaling cascade networks, changes in 3D genome modularity, and differential expression and functionalities of transcription factors and noncoding RNAs. Many of these identified genes and regulatory molecules showed no significant change in their expression or a single epigenomic modality, emphasizing the power of integrative multimodal and multiomic analysis using patient samples.

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“…Although chromatin exposure and high transcription rates are found in embryonic stem cells, upon initiation of differentiation, cells acquire markers for transcriptional repression. A recent meta-analysis of human lung cancer samples in The Cancer Genome Atlas found that genes represented in the “Rhythmic Process” were associated with immune activation, circadian rhythm, and carcinogenic pathways ( 99 ). With this information in combination with enriched processes of pattern specification, regionalization, and various organ development processes, we hypothesize that this population represents a dedifferentiated group of fibroblast-like cells that are more involved in the tumor microenvironment than the GOBP terms suggest.…”

Section: Resultsmentioning

confidence: 99%

Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model

McLean,

Meudt,

Lopez Rivera

et al. 2023

Front. Oncol.

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Neurofibromatosis Type 1 (NF1) is one of the most common genetically inherited disorders that affects 1 in 3000 children annually. Clinical manifestations vary widely but nearly always include the development of cutaneous, plexiform and diffuse neurofibromas that are managed over many years. Recent single-cell transcriptomics profiling efforts of neurofibromas have begun to reveal cell signaling processes. However, the cell signaling networks in mature, non-cutaneous neurofibromas remain unexplored. Here, we present insights into the cellular composition and signaling within mature neurofibromas, contrasting with normal adjacent tissue, in a porcine model of NF1 using single-cell RNA sequencing (scRNA-seq) analysis and histopathological characterization. These neurofibromas exhibited classic diffuse-type histologic morphology and expected patterns of S100, SOX10, GFAP, and CD34 immunohistochemistry. The porcine mature neurofibromas closely resemble human neurofibromas histologically and contain all known cellular components of their human counterparts. The scRNA-seq confirmed the presence of all expected cell types within these neurofibromas and identified novel populations of fibroblasts and immune cells, which may contribute to the tumor microenvironment by suppressing inflammation, promoting M2 macrophage polarization, increasing fibrosis, and driving the proliferation of Schwann cells. Notably, we identified tumor-associated IDO1+/CD274+ (PD-L1)+ dendritic cells, which represent the first such observation in any NF1 animal model and suggest the role of the upregulation of immune checkpoints in mature neurofibromas. Finally, we observed that cell types in the tumor microenvironment are poised to promote immune evasion, extracellular matrix reconstruction, and nerve regeneration.

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Integrative Molecular Analyses of an Individual Transcription Factor-Based Genomic Model for Lung Cancer Prognosis

Cited by 3 publications

References 37 publications

Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma

Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma

Comprehensive multimodal and multiomic profiling reveals epigenetic and transcriptional reprogramming in lung tumors

Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model

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