Lymphangiogenesis-related gene signature-based risk model for prognostic assessment of cervical cancer: immune-metabolic characterization and molecular subtype analysis.
BACKGROUND: Lymphangiogenesis promotes tumor dissemination and may shape the immune contexture of cervical cancer, yet lymphangiogenesis-related prognostic stratification and its immunometabolic implications remain insufficiently defined in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). METHODS: TCGA-CESC transcriptomes and clinical data were obtained from UCSC Xena and integrated with normal cervix tissues from the Genotype-Tissue Expression Project after batch correction. Prognostic LYMRGs were first identified from the differentially expressed set using univariable Cox proportional hazards analysis. Candidate genes were then reduced using an L1-regularized Cox model (Least Absolute Shrinkage and Selection Operator), and the remaining markers were entered into a multivariable Cox regression to obtain the final coefficients and compute an individualized risk score. The model's prognostic value was further assessed in an independent Gene Expression Omnibus dataset. In addition, expression patterns of the signature genes were leveraged for molecular subtyping of TCGA samples via non-negative matrix factorization (NMF). Immune infiltration and immunotherapy-associated characteristics were interrogated through a multi-algorithm strategy (single-sample gene set enrichment analysis, CIBERSORT, ESTIMATE, Tumor Immune Dysfunction and Exclusion (TIDE), and Immunophenoscore . Additional analyses included pathway enrichment (GSEA/GO/KEGG), drug sensitivity prediction (pRRophetic/CellMiner), and ceRNA network analysis. RESULTS: A six-gene LYMRG signature robustly stratified survival. High-risk patients had significantly worse overall survival in The Cancer Genome Atlas with AUCs of 0.819/0.801/0.801 at 1/3/5 years, and in GSE52903 (P = 0.001) with AUCs of 0.733/0.719/0.725. NMF identified two subtypes with distinct prognosis (P = 0.01) and divergent immune landscapes. Risk groups and subtypes exhibited consistent differences in immune infiltration, checkpoint expression, TIDE/IPS patterns, and pathway enrichment. Predicted chemosensitivity differed by risk group, and the ceRNA network suggested candidate upstream lncRNA regulators of the signature. CONCLUSION: A lymphangiogenesis-related six-gene model enables clinically meaningful prognostic stratification of CESC and links lymphangiogenesis programs to distinct tumor immune phenotypes and therapeutic vulnerabilities.