Development and external validation of an 18-gene tertiary lymphoid structure-related prognostic signature in gastric cancer.
- 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- 2Department of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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.
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BibTeX
@article{han2026development,
title = {{Development and external validation of an 18-gene tertiary lymphoid structure-related prognostic signature in gastric cancer.}},
author = {Xiaying Han and Qimiao Chen and Zhixing Hao and Jing Chen and Jia Qi and Jian Chen},
journal = {Translational cancer research},
year = {2026},
month = sep,
doi = {10.21037/tcr-2026-2004},
url = {https://europepmc.org/article/MED/42997890},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Development and external validation of an 18-gene tertiary lymphoid structure-related prognostic signature in gastric cancer.
AU - Xiaying Han
AU - Qimiao Chen
AU - Zhixing Hao
AU - Jing Chen
AU - Jia Qi
AU - Jian Chen
PY - 2026
DA - 2026/09/28
JO - Translational cancer research
DO - 10.21037/tcr-2026-2004
UR - https://europepmc.org/article/MED/42997890
AB - 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.
SN - 2218-676X
SN - 2219-6803
ER -