Abstract
Long non-coding RNA (lncRNA) plays a crucial role in modulating genome instability, immune characteristics, and cancer progression, within which genome instability was identified as a critical regulator in tumorigenesis and tumor progression. However, the existing accounts fail to detail the regulatory role of genome instability in lung adenocarcinoma (LUAD). We explored the clinical value of genome instability-related lncRNA in LUAD with multi-omics bioinformatics analysis. We extracted the key genome instability-related and LUAD-related gene modules using weighted gene co-expression network analysis (WGCNA) and established a competing endogenous RNA (ceRNA) network using four lncRNAs (LINC01224, LINC00346, TRPM2-AS, and CASC9) and seven target mRNAs (CCNF, PKMYT1, GCH1, TK1, PSAT1, ADAM33, and DDX11). We found that LINC01224 is primarily located in the cytoplasm and that LINC00346 and TRPM2-AS are primarily located in the nucleus (CASC9 unknown). We found that all 11 genes were positively related to tumor mutational burden and involve drug resistance, cancer stemness, and tumor microenvironment infiltration. Additionally, an eight-lncRNA genome instability-related lncRNA signature was established and validated, predicting the overall survival and immunotherapy outcomes in LUAD. To conclude, we discovered that sponging microRNA, genome instability-related lncRNA functions as ceRNA, modulating genomic integrity. This research provides clinical references for LUAD immunotherapy and prognosis and interprets a potential genome instability-related ceRNA regulatory network in which LINC01224-miR-485-5p/miR-29c-3p-CCNF-RRM2 and LINC01224-miR485-5p-PKMYT1-CDK1 axes were the most promising pathways. However, the potential mechanisms underlying our findings still need biological validation through in vitro and in vivo experiments.
Highlights
At present, the incidence and mortality of lung cancer rank first among malignant tumors worldwide
Transcriptome profiling (gene expression quantification (RNAseq, which was preprocessed by fragments per kilobase of an exon model per million mapped fragments (FPKM)) and microRNA expression quantification), and simple nucleotide variation (SNV, Masked Somatic Mutation detected by VarScan 2) from the lung adenocarcinoma (LUAD) project of The Cancer Genome Atlas (TCGA) database were download through the Genomic Data Commons Data Portal website
Given that weighted gene co-expression network analysis (WGCNA) was used to extract key gene modules related to genome instability and tumorigenesis, we first intersected the module that was most related to genome instability, the top three modules that were most related to tumorigenesis, and the genome instabilityrelated lncRNA (GlncR) to screen the crucial long non-coding RNA (lncRNA) that are related to genome instability and LUAD tumorigenesis
Summary
The incidence and mortality of lung cancer rank first among malignant tumors worldwide. Current clinical practice has demonstrated the prominent effect of immunotherapy, especially after the discovery of immune checkpoint, primarily including programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4). A recent prospective randomized clinical trial, KEYNOTE-042, demonstrated that pembrolizumab achieved a significantly longer OS in advanced LUAD patients even with low PD-L1 expression (Mok et al, 2019). Immune checkpoint inhibitor (ICI) expense significantly burdens patients and government health insurance (Carbone et al, 2017; Niu et al, 2020), and the median objective response rate is only 48.5% in PD-L1-overexpressing (≥50%) NSCLC (Frost et al, 2021). There is still an urgent need to explore more effective immunotherapy biomarkers
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