ArticleJournal of thoracic disease2026
An early invasive signature from the adenocarcinoma in situ-to-invasive adenocarcinoma single-cell trajectory stratifies stage I lung adenocarcinoma overall survival.
Article in Journal of thoracic disease, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Stage I lung adenocarcinoma (LUAD) shows significant variability in prognosis that the traditional tumor-node-metastasis (TNM) system fails to fully detect. Most current prognostic signatures are based on bulk-level statistical analyses and do not have a clear biological basis. This research focused on identifying an early-invasive gene set (EIGS) through single-cell pseudotime trajectory analysis and creating a simple risk score for better prognostic classification in stage I LUAD. Methods: Single-cell RNA sequencing data from adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC) were analyzed to reconstruct malignant epithelial pseudotime trajectories using Monocle 2. A 200-gene EIGS was derived from the invasion-associated branch and condensed into a multi-gene EIGS Score via stepwise Cox forward selection with Ridge penalization in The Cancer Genome Atlas (TCGA) stage I training cohort (n=269). The model was externally validated in three independent cohorts (GSE37745, n=70; GSE50081, n=92; GSE72094, n=254) and assessed by pooled analysis. Immune microenvironment characterization, drug-sensitivity profiling, and virtual gene-knockout analysis were conducted to assess the biological and therapeutic relevance of the EIGS Score. Results: The EIGS Score stratified overall survival (OS) in the training cohort [hazard ratio (HR) = 4.53, P<0.001; concordance index (C-index) =0.698] and was confirmed in pooled external validation across three cohorts [pooled OS: HR =2.50, P<0.001, C-index =0.640; pooled disease-free survival (DFS): HR =3.26, P=0.001, C-index =0.653]. Multivariable Cox regression confirmed the EIGS Score as an independent prognostic factor after adjusting for age, sex, and substage (HR =1.93; P<0.001). High-EIGS tumors exhibited lower immune infiltration scores, enrichment of the high-plasticity cell state, and a selective drug-sensitivity profile. The virtual knockout of Conclusions: The EIGS Score, derived from a single-cell invasive trajectory, consistently demonstrates prognostic value in stage I LUAD and may complement existing risk-stratification tools, though further prospective validation is needed.
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