An inflammation-associated five-gene expression signature stratifies survival and immune states in lung adenocarcinoma: an integrative public-cohort analysis
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Background
Inflammation and the tumor immune microenvironment contribute to lung adenocarcinoma (LUAD) progression, but the relationship among inflammation-linked transcriptional heterogeneity, patient survival, and immune-state variation remains incompletely defined.
Objective
We aimed to identify inflammation-associated LUAD subtypes, derive a parsimonious survival-stratification signature, and characterize its immune and pathway context across public transcriptomic cohorts.
Methods
Expression profiles and clinical data were obtained from TCGA-LUAD, GTEx normal lung, and GEO datasets GSE11969, GSE30219, GSE31210, and GSE40791. A curated set of 596 inflammation-related genes was used for consensus clustering. Differential-expression analysis, functional enrichment, univariate Cox regression, and LASSO-Cox modeling were integrated to construct a gene-expression risk score. The prognostic dataset comprised 730 cases and was randomly divided into training (n=502) and internal-validation (n=228) sets; 85 GSE30219 cases formed an external-validation cohort. Immune-cell enrichment, gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and pan-cancer analyses were used for biological contextualization.
Results
The LUAD-versus-control comparison identified 1,305 differentially expressed genes, including 498 upregulated and 807 downregulated genes. Consensus clustering resolved two inflammation-associated subtypes and 67 subtype-associated genes, of which 64 were higher and 3 were lower in Cluster 1 relative to Cluster 2. Thirty-three genes overlapped between the tumor-control and subtype contrasts. LASSO-Cox regression selected CHRDL1, FDCSP, CXCL13, CYP4B1 , and S100P . The 1-, 3-, and 5-year areas under the time-dependent receiver operating characteristic curve were 0.6625, 0.6581, and 0.6658 in the training set; 0.7422, 0.6537, and 0.6761 in internal validation; and 0.6560, 0.6387, and 0.6753 in external validation. Risk groups differed across multiple T-cell, B-cell, natural-killer-cell, myeloid, dendritic-cell, macrophage, and granulocyte signatures. Positive GSEA signals included cell cycle (normalized enrichment score [NES]=2.67; adjusted P=1.42×10 −8 ), DNA replication (NES=2.52; adjusted P=2.52×10 −7 ), and mismatch repair (NES=2.20; adjusted P=1.77×10 −4 ).
Conclusions
The five-gene expression score separated LUAD survival groups and captured coordinated proliferative and immune transcriptional states. Its moderate discrimination supports further biological and clinical validation rather than immediate clinical application.
Brief Summary
Public LUAD transcriptomes identified two inflammation-associated subtypes and a five-gene score comprising CHRDL1, FDCSP, CXCL13, CYP4B1 , and S100P that separated survival groups and marked distinct proliferative and immune expression programs.
