A P-body-related risk score predicts prognosis and immune microenvironment in lung adenocarcinoma.

BACKGROUND: Processing bodies (P-bodies) are cytoplasmic granules involved in post-transcriptional gene regulation and play pivotal roles in carcinogenesis. However, the clinical significance of P-body-associated genes in lung adenocarcinoma (LUAD) remains poorly understood. This study aimed to investigate the clinical prognostic significance and potential biological roles of P-body-associated genes in LUAD, and establish a gene-based prognostic model for clinical application.

METHODS: Twenty-four core P-body-related genes were curated from a user-friendly database RNAgranuleDB. Using transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) LUAD cohort, univariate Cox regression was performed to screen prognostic genes, followed by least absolute shrinkage and selection operator (LASSO)-Cox regression with ten-fold cross-validation to construct a P-body-related risk score based on five retained genes (MOV10, PCBP1, PCBP2, YBX1, YWHAG). The prognostic value of this score was evaluated in TCGA and validated in five independent Gene Expression Omnibus (GEO) cohorts. Functional implications were explored through gene set variation analysis (GSVA) and reverse-phase protein array (RPPA) analysis. Immune microenvironment characteristics were assessed using single-sample gene set enrichment analysis (ssGSEA).

RESULTS: The P-body-related risk score served as an independent prognostic factor in LUAD, with high score significantly associated with worse overall survival (OS), progression-free interval (PFI), and disease-specific survival (DSS) in the TCGA cohort. These findings were consistently validated across five independent GEO cohorts. Functionally, high scores were associated with enhanced mRNA editing, activation of cell cycle pathways (G2/M checkpoint, E2F targets), PI3K-AKT-mTOR signaling, and DNA repair activity, as well as increased genomic instability markers including tumor mutational burden (TMB), tumor neoantigen burden (TNB), and homologous recombination deficiency (HRD). Regarding the tumor immune microenvironment, low score correlated with an immunologically active phenotype characterized by increased infiltration of CD8+ T cells, B cells, and dendritic cells (validated by both ssGSEA and xCell), and upregulation of antigen presentation genes. In contrast, high score was associated with an immunosuppressive phenotype and elevated expression of immune checkpoint molecules including programmed death-ligand 1 (PD-L1) and CD276.

CONCLUSIONS: We developed and validated a P-body-related five-gene risk score that independently predicts LUAD prognosis and stratifies immune phenotypes. As these genes have extra-P-body functions, the score serves as a transcriptomic proxy for P-body component enrichment, not a direct measure of P-body activity. Despite this limitation, it offers a clinically useful tool for risk stratification and mechanistic hypotheses.