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  • Integrated Multi-Cohort Transcriptomic Analysis Identifies BST2 as a Candidate Immune-Associated Biomarker in Non-Small cell lung cancer

  • Salehe Amiri,1,* Babak Jahangiri,2 Elahe Asadollahi,3 Alireza Zomorodipour,4
    1. Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
    2. Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
    3. Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
    4. Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran


  • Introduction: Lung cancer remains one of the leading causes of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) accounting for approximately 85% of all lung cancer cases. Most patients with NSCLC are diagnosed at advanced stages, when therapeutic options are limited and prognosis is poor, resulting in low five-year survival rates. The lack of sensitive and specific approaches for early detection remains a major challenge in improving clinical outcomes. Therefore, the identification of reliable molecular biomarkers with potential diagnostic, prognostic, and therapeutic relevance is of considerable clinical importance, particularly for individuals at high risk of developing lung cancer. This study aimed to identify and characterize potential molecular biomarkers for the early diagnosis, prognosis, and therapeutic targeting of NSCLC through the integrative analysis of publicly available high-throughput gene expression datasets using bioinformatics and statistical approaches. By integrating transcriptomic data across independent datasets, the study sought to identify robust differentially expressed genes and molecular signatures that may provide insights into NSCLC pathogenesis and serve as candidate biomarkers for improved disease detection and management.
  • Methods: Publicly available transcriptomic datasets comprising human NSCLC and non-cancerous tissue samples were obtained from the Gene Expression Omnibus (GEO), incorporating both RNA-seq and microarray platforms. Differentially expressed genes were identified across independent cohorts, and concordant expression patterns were investigated to identify robust NSCLC-associated candidates. Protein–protein interaction networks were constructed using STRING and visualized in Cytoscape, with network topology assessed using CytoHubba. Functional characterization was performed using Gene Ontology and KEGG pathway enrichment through DAVID and Enrichr, complemented by Gene Set Enrichment Analysis (GSEA). BST2 expression and its clinical-stage associations were further evaluated using TCGA pan-cancer datasets, and relationships with selected Immune & Interferon Signaling, Cell Cycle and Mitotic Regulation genes were examined. In vitro expression of BST2 was additionally evaluated across 3 representative cancer cell lines, including the NSCLC cell line CALU-6.
  • Results: Integrative analysis across independent transcriptomic cohorts identified a reproducible NSCLC-associated transcriptional signature enriched for immune and interferon-responsive genes. BST2 emerged as a highly connected component of an immune/interferon-associated network containing IFI35, IFI6, MX1, and OAS3 as well as chemokines such as CXCL11. Functional enrichment analyses identified interferon-responsive and innate immune pathways, including Type II Interferon signaling, while GSEA demonstrated enrichment of proliferative programs, including E2F target and G2/M checkpoint pathways, together with interferon-α and interferon-γ response signatures. TCGA analyses further demonstrated persistent BST2 expression across NSCLC clinical stages and positive associations with genes involved in cell cycle and proliferation including MELK, PBK, and BUB1B. Among the three examined cancer cell lines, Calu-6 exhibited the highest endogenous BST2 expression.
  • Conclusion: Across independent transcriptomic datasets, BST2 consistently associated with immune/interferon-responsive and tumor-associated transcriptional programs in NSCLC. Its network connectivity and association with inflammatory, proliferative, chemokine related signatures support BST2 as a candidate immune-associated biomarker and a potential subject for further mechanistic investigation. However, functional perturbation and independent clinical validation are required to determine whether BST2 has a tumor-cell-intrinsic regulatory role or predictive/prognostic utility and to establish its potential relevance to NSCLC immunotherapy.
  • Keywords: Non-small cell lung cancer, BST2, Bioinformatic analysis, Meta-Analysis, Immune response

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