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Prognosis Prediction Through an Integrated Analysis of Single-Cell and Bulk RNA-Sequencing Data in Triple-Negative Breast Cancer

ABSTRACT: Background: Genomic and antigenic heterogeneity pose challenges in the precise assessment of outcomes of triple-negative breast cancer (TNBC) patients. Thus, this study was designed to investigate the cardinal genes related to cell differentiation and tumor malignant grade to advance the prognosis prediction in TNBC patients through an integrated analysis of single-cell and bulk RNA-sequencing (RNA-seq) data. Methods: We collected RNA-seq and microarray data of TNBC from two public datasets. Using single-cell pseudotime analysis, differentially expressed genes (DEGs) among trajectories from 1534 cells of 6 TNBC patients were identified as the potential genes crucial for cell differentiation. Furthermore, the grade- and tumor mutational burden (TMB)-related DEGs were explored via a weighted correlation network analysis using the Molecular Taxonomy of Breast Cancer International Consortium dataset. Subsequently, we utilized the DEGs to construct a prognostic signature, which was validated using another independent dataset. Moreover, as gene set variation analysis indicated the differences in immune-related pathways between different risk groups, we explored the immune differences between the two groups. Results: A signature including 10 genes related to grade and TMB was developed to assess the outcomes of TNBC patients, and its prognostic efficacy was prominent in two cohorts. The low-risk group generally harbored lower immune infiltration compared to the high-risk group. Conclusion: Cell differentiation and grade- and TMB-related DEGs were identified using single-cell and bulk RNA-seq data. A 10-gene signature for prognosis prediction in TNBC patients was constructed, and its performance was excellent. Interestingly, the signature was found to be closely related to tumor immune infiltration, which might provide evidence for the crucial roles of immune cells in malignant initiation and progression in TNBC.

SUBMITTER: Wang X

PROVIDER: S-EPMC9283578 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveImmunotherapy has brought significant clinical benefits to a subset of patients, but has thus far been disappointing in the treatment of immunologically "cold" tumors. Existing biomarkers that can precisely identify these populations are insufficient. In this context, a potential cold tumor microenvironment (TME) marker FARSB was investigated to reveal its impact on TME and patients' response to immunotherapy across pan-cancer.MethodsThe expression levels and mutational landscape of FARSB in pan-cancer were investigated. Kaplan-Meier and univariate Cox regression analyses were applied to analyze the prognostic significance of FARSB. Pathways affected by FARSB were investigated by gene set enrichment and variation analysis. The relationship between FARSB expression and immune infiltration was examined using the TIMER2 and R packages. Single-cell RNA sequencing (scRNA-seq) data of several cancer types from GSE72056, GSE131907, GSE132465, GSE125449 and PMID32561858 were analyzed to validate the impact of FARSB on the TME. The predictive effect of FARSB on immunotherapy efficacy was explored in 3 immune checkpoint inhibitors (ICIs)- treated cohorts (PMID32472114, GSE176307, and Riaz2017).ResultsFARSB expression was significantly higher in 25 tumor tissues than in normal tissues and was associated with poor prognosis in almost all tumor types. FARSB expression exhibited a strong association with several DNA damage repair pathways and was significantly associated with TP53 mutation in lung adenocarcinoma (P < 0.0001, OR=2.25). FARSB characterized a typical immune desert TME and correlated with impaired expression of chemokines and chemokines receptors. Large-scale scRNA-seq analysis confirmed the immunosuppressive role of FARSB and revealed that FARSB potentially shapes the cold TME by impeding intercellular interactions. In 3 ICI-treated cohorts, FARSB demonstrated predictive value for immunotherapy.ConclusionThis study provides a pan-cancer landscape of the FARSB gene by integrated single-cell and bulk DNA sequencing analysis and elucidates its biological function to promote DNA damage repair and construct the immune desert TME, suggesting the potential value of FARSB as a novel marker for stratifying patients with poor immunotherapeutic benefits and "cold" TME.

Dataset Information

Prognosis Prediction Through an Integrated Analysis of Single-Cell and Bulk RNA-Sequencing Data in Triple-Negative Breast Cancer

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