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Identification of immunotherapy biomarkers for improving the clinical outcome of homologous recombination deficiency patients with lung adenocarcinoma.

ABSTRACT: Homologous recombination deficiency (HRD) is a common molecular signature of genomic instability and has been shown to be a biomarker for targeted therapies. However, there is a lack of studies on the role of HRD changes in lung adenocarcinoma (LUAD) transcriptomics. HRD scores were determined using single nucleotide polymorphism (SNP) array data from LUAD patients from The Cancer Genome Atlas (TCGA) database. Transcriptional data from patients with different scores were analyzed to identify biomarkers associated with HRD. Candidate biomarkers were validated using Gene Expression Omnibus (GEO)-sourced datasets and an immunotherapy cohort. According to the bulk transcriptome and clinical characteristics of 912 LUAD patients and Single-cell RNA-seq of 9 LUAD patients from TCGA and GEO databases, we observed increased MS4A6A expression in HRD tumors; high MS4A6A expression predicted improved survival outcomes. Furthermore, a comprehensive analysis of the tumor immune microenvironment (TIME) revealed a positive correlation between MS4A6A expression and neoantigen loading and immune cell infiltration. Additionally, the immunotherapy cohort confirmed the possibility of using MS4A6A as a biomarker. Collectively, we suggest that MS4A6A is associated with HRD and provide a new perspective toward identifying promising biomarkers for immunotherapy.

SUBMITTER: Zhou X

PROVIDER: S-EPMC10496994 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Identification of immunotherapy biomarkers for improving the clinical outcome of homologous recombination deficiency patients with lung adenocarcinoma.

Zhou Xiang X Xu Rongjian R Lu Tong T Xu Ran R Wang Chenghao C Peng Bo B Chang Xiaoyan X Shen Zhiping Z Wang Kaiyu K Shi Jiaxin J Zhao Jiaying J Zhang Lin-You LY

Aging 20230811 16

Homologous recombination deficiency (HRD) is a common molecular signature of genomic instability and has been shown to be a biomarker for targeted therapies. However, there is a lack of studies on the role of HRD changes in lung adenocarcinoma (LUAD) transcriptomics. HRD scores were determined using single nucleotide polymorphism (SNP) array data from LUAD patients from The Cancer Genome Atlas (TCGA) database. Transcriptional data from patients with different scores were analyzed to identify bio ...[more]

PMID: 37578930

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Project description:BackgroundNon-small cell lung cancer with homologous recombination deficiency (HRD) was revealed to have better response to immunotherapy. Long non-coding RNAs (lncRNAs) modulate multiple processes including HRD acting as potential biomarkers in tumors. The function of HRD-associated lncRNAs in lung cancer arouses our interests.MethodsTwo independent cohorts were enrolled containing 838 lung adenocarcinoma (LUAD) patients. HRD-associated lncRNAs were defined as the lncRNAs that were differential expressed in high-HRD group and low-HRD group which were classified in accordance with the HRD score. The least absolute shrinkage and selection operator cox regression was employed to construct a signature according to prognostic HRD-associated lncRNAs. The signature robustness was evaluated by using the prognosis analysis, multivariate-cox analysis, ROC curve, and nomogram. The participating pathways were estimated by gene set enrichment analysis and KEGG pathway analysis. The infiltration of immune cells was estimated by using xCell. The tumor immune dysfunction and exclusion (TIDE) and immunophenoscore (IPS) were both utilized for the prediction of immunotherapy response.ResultsSeventeen HRD-associated lncRNAs were screened to classify the LUAD patients into two groups with variant survival that inferior overall survival was found in high-risk patients comparing to those with low-risk. Our model not only was the independent prognostic factor in LUAD but also had better performance on the prognosis prediction when making a comparison with other clinical and molecular signatures. Additionally, the high-risk group was suggested to have increased genomic instability and less response to immunotherapy.ConclusionA great predicative efficient prognostic signature was established based on 17 HRD-associated lncRNAs in LUAD. The signature might be the predictor for genomic instability and immunotherapy response in LUAD. Our findings provided new insight for the improvement of clinical stratification in LUAD.

Project description:ObjectiveThe current study aims to identify the dysregulated pathway involved in carcinogenesis and the essential survival-related dysregulated genes among this pathway in the early stage of lung adenocarcinoma (LUAD).Patients and methodsData from The Cancer Genome Atlas (TCGA) including 526 tumor tissues of LUAD and 59 healthy lung tissues were analyzed to gain differentially expressed genes (DEGs). Gene ontology (GO) analysis was conducted with DAVID, while the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs was performed, followed by gene set enrichment analysis (GSEA) methods. Survival analysis was implemented in TCGA dataset and validated in Gene Expression Omnibus (GEO) cohort GSE50081, which includes 127 patients with stage I LUAD.ResultsGSEA enrichment analysis suggested that homologous recombination repair (HRR) pathway was significantly enriched. Subsequent KEGG pathway enrichment analysis indicated the significant up-regulation of HRR pathway in patients with T1 stage LUAD. Retrieved in Gene database, RAD54L is involved in HRR pathway and were recognized to be significantly differentially expressed in T1 stage LUAD in our study. The survival analysis indicated that high expression of RAD54L was significantly related to worse overall survival in patients with T1 stage LUAD (TCGA cohort: HR=2.10, 95% CI [1.47-2.98], P = 0.001; GSE50081 validation cohort: HR = 2.61, 95% CI [1.51-4.52], P = 0.002). Multivariate cox regression analysis indicated that RAD54L is an independent prognostic factor in the early-stage LUAD.ConclusionHRR pathway is up-regulated in LUAD, among which the expression of RAD54L was found to be significantly differentially expressed in T1 stage tumor tissue. Patients with high expression of RAD54L were associated with worse overall survival in the TCGA cohort and validation cohort. This study suggests a potential mechanism of lung cancer progression and provide a budding prognostic factor and treatment target in early-stage LUAD.

Project description:BackgroundRadiation therapy is one of the most common treatments for non-small cell lung cancer (NSCLC). However, the insensitivity of some tumor cells to radiation is one of the major reasons for the poor efficacy of radiotherapy and the poor prognosis of patients, and exploring the underlying mechanisms behind radioresistance is the key to solving this clinical challenge. This study aimed to identify the molecules associated with radioresistance in lung adenocarcinoma (LUAD), identified thyroid hormone receptor interactor 13 (TRIP13) as the main target initially, and explored whether TRIP13 is related to radioresistance in LUAD and the specific mechanism, with the aim of providing theoretical basis and potential targets for the combination therapy of LUAD patients receiving radiotherapy in the clinic.MethodsThree datasets, GSE18842, GSE19188 and GSE33532, were selected from the Gene Expression Omnibus (GEO) database and screened for differentially expressed genes (|log FC|>1.5, P<0.05) in each of the three datasets using the R 4.1.3 software, and then Venn diagram was used to find out the differentially expressed genes common to the three datasets. The screened differential genes were then subjected to protein-protein interaction (PPI) analysis and module analysis with the help of STRING online tool and Cytoscape software, and survival prognosis analysis was performed for each gene with the help of Kaplan-Meier Plotter database, and the TRIP13 gene was identified as the main molecule for subsequent studies. Subsequently, the human LUAD cell line H292 was irradiated with multiple X-rays using a sub-lethal dose irradiation method to construct a radioresistant cell line, H292DR. The radioresistance of H292DR cells was verified using cell counting kit-8 (CCK-8) assay and clone formation assay. The expression levels of TRIP13 in H292 and H292DR cells were measured by Western blot. Small interfering RNA (siRNA) was used to silence the expression of TRIP13 in H292DR cells and Western blot assay was performed. The clone formation ability and migration ability of H292DR cells were observed after TRIP13 silencing, followed by the detection of changes in the expression levels of proteins closely related to homologous recombination, such as ataxia telangiectasia mutated (ATM) protein.ResultsScreening of multiple GEO datasets, validation of external datasets and survival analysis revealed that TRIP13 was highly expressed in LUAD and was associated with poor prognosis in LUAD patients who had received radiation therapy. And the results of gene set enrichment analysis (GSEA) of TRIP13 suggested that TRIP13 might be closely associated with LUAD radioresistance by promoting homologous recombination repair after radiation therapy. Experimentally, TRIP13 expression was found to be upregulated in H292DR, and silencing of TRIP13 was able to increase the sensitivity of H292DR cells to radiation.ConclusionsTRIP13 is associated with poor prognosis in LUAD patients treated with radiation, possibly by promoting a homologous recombination repair pathway to mediate resistance of LUAD cells to radiation.

Dataset Information

Identification of immunotherapy biomarkers for improving the clinical outcome of homologous recombination deficiency patients with lung adenocarcinoma.

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Identification of immunotherapy biomarkers for improving the clinical outcome of homologous recombination deficiency patients with lung adenocarcinoma.

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