{
  "abstract": "Tertiary lymphoid structures (TLS) contribute to local antitumor immunity, but TLS-related transcriptional signals do not directly measure histological TLS abundance or maturation. This study aimed to develop and externally evaluate a biologically constrained TLS-related gene (TLSRG) signature for prognostic stratification in gastric cancer and characterize its associated immune-stromal programmes. Transcriptomic and clinical data from 350 patients in The Cancer Genome Atlas stomach adenocarcinoma (TCGA-STAD) cohort and 431 patients in GSE84437 were used for development and external evaluation, respectively. Least absolute shrinkage and selection operator (LASSO)-Cox regression was applied to a predefined 39-gene panel. Overall survival (OS) was assessed using Kaplan-Meier analysis, Cox regression, the concordance index (C-index), and time-specific receiver operating characteristic (ROC) analysis. Additional analyses evaluated TLS-related cell-state and functional transcriptional surrogates, model-gene-overlap-excluded scores, cross-cohort association networks, 18-gene co-expression, and area under the curve (AUC) uncertainty using 2,000 patient-level bootstrap resamples. A combined clinical model underwent internal cross-validation using the precomputed risk score. The 18-gene signature separated survival in TCGA-STAD [high vs. low risk: hazard ratio (HR) =3.108; 95% confidence interval (CI): 2.178-4.436] and GSE84437 (HR =1.410; 95% CI: 1.071-1.856). The score remained associated with survival after age, sex, and pathological stage or tumor-node-metastasis (TNM) adjustment in separate TCGA-STAD models. External 1-, 3-, and 5-year AUCs were 0.526 (95% CI: 0.443-0.607), 0.597 (0.540-0.654), and 0.606 (0.548-0.661), indicating limited discrimination, particularly at 1 year. Risk was consistently associated with epithelial-mesenchymal transition (EMT)/stromal and angiogenesis scores and with CXCL12 expression after excluding CXCR4 from the two-gene axis score. Cell-state and immune-function contrasts were cohort-dependent rather than uniformly reduced in high-risk tumors. The 18-gene network retained 102 consensus co-expression edges; CXCL13, ICOS, PDCD1, CD79A, and CCR7 had the highest connectivity, whereas CXCR4 had the largest model coefficient. The combined model had an internal C-index of 0.704 vs. 0.617 for clinical variables alone. The TLSRG signature was associated with survival and reproducible stromal/angiogenic transcriptional features, although external discrimination was modest. Prospective spatial and functional studies are needed to determine its relationship with TLS maturation and clinical utility.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.",
    "Department of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xiaying Han"
    },
    {
      "affs": [
        0
      ],
      "name": "Qimiao Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhixing Hao"
    },
    {
      "affs": [
        0
      ],
      "name": "Jing Chen"
    },
    {
      "affs": [
        1
      ],
      "name": "Jia Qi"
    },
    {
      "affs": [
        0
      ],
      "name": "Jian Chen"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4784ww43dy9fs.bib",
  "cited_by": 0,
  "doi": "10.21037/tcr-2026-2004",
  "fulltext_url": "https://europepmc.org/articles/PMC13743212",
  "id": "4784ww43dy9fs",
  "issns": [
    "2218-676X",
    "2219-6803"
  ],
  "landing_url": "https://europepmc.org/article/MED/42997890",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7223364497",
  "pdf_url": "https://europepmc.org/articles/PMC13743212?pdf=render",
  "pmcid": "PMC13743212",
  "pmid": "42997890",
  "published": "2026-09-28",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/4784ww43dy9fs.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T15:20:41Z",
      "native_id": "MED:42997890",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42997890"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Cancer Immunotherapy and Biomarkers",
      "subfield": "oncology"
    }
  ],
  "title": "Development and external validation of an 18-gene tertiary lymphoid structure-related prognostic signature in gastric cancer.",
  "title_text": "Development and external validation of an 18-gene tertiary lymphoid structure-related prognostic signature in gastric cancer.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T15:20:41Z",
  "url": "https://research.draconitic.com/paper/4784ww43dy9fs",
  "venue": "Translational cancer research",
  "versions": []
}