Development of an early diagnostic model for gastric cancer combining serum cytokine profiles with conventional tumor markers: a case–control study

Background Early detection of gastric cancer (GC) remains challenging, and conventional serum tumor markers show limited sensitivity for precancerous gastric lesions. Inflammatory cytokines change during tumorigenesis and may provide complementary information for noninvasive screening. We evaluated whether serum cytokine profiling combined with routine tumor markers could improve discrimination across the spectrum from healthy mucosa to precancerous lesions and early GC. Methods In this single-center, cross-sectional case–control study, 165 participants were enrolled: 60 patients with GC (including 15 high-grade intraepithelial neoplasia [HGIN]/carcinoma in situ ), 50 individuals with gastric precancerous lesions (GPL; 25 atrophic gastritis [AG] and 25 intestinal metaplasia [IM]), and 55 healthy controls (HC). Serum levels of nine cytokines (IL-1ra, IL-6, IL-7, IL-8, IL-10, IL-16, IL-17, IL-21, and necrosis factor-α [TNF-α] ) were quantified by ELISA, and five conventional tumor markers (carcinoembryonic antigen [CEA], carbohydrate antigen 19–9 [CA19-9], carbohydrate antigen CA125 [CA125], carbohydrate antigen CA72–4 [CA72-4] andalpha fetoprotein [AFP] ) were recorded. Group comparisons were performed using the Kruskal–Wallis test followed by multiple-testing correction. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis. Combined models were constructed using multivariable logistic regression and evaluated using predicted probabilities. Results Compared with HC, GC cases exhibited higher IL-6, IL-8, IL-10, IL-16, IL-17, IL-21, and TNF-α, and lower IL-1ra and IL-7. GPL cases showed increased IL-16 and IL-17 and decreased IL-7,IL-16 correlated moderately with IL-10(r=0.62), suggesting coordinated inflammatory–immunoregulatory signaling. As individual markers, IL-16 yielded an AUC of 0.91 for GC versus HC, IL-7 yielded an AUC of 0.76 for GC versus GPL, and IL-16 and IL-17 showed value for detecting GPL (AUCs 0.74 and 0.73, respectively). Multimarker combinations improved discrimination: IL-6+IL-7+IL-16+CEA reached an AUC of 0.93 for GC versus GPL; IL-6+IL-16+IL-17 reached an AUC of 0.92 for GPL versus HC; and an integrated model discriminating GC from HC achieved an AUC of 0.97. Bootstrap internal validation showed optimism-corrected AUCs of 0.902, 0.889, and 0.927 for these three combined models, respectively SHAP-based ranking indicated that IL-16, IL-6, CEA, and IL-7 were the main contributors to the 12-analyte model, whereas IL-21 had relatively low marginal contribution. Conclusions Serum inflammatory cytokine patterns change early during gastric carcinogenesis. Combining cytokine profiles with conventional tumor markers substantially enhances noninvasive discrimination of precancerous lesions and early GC. However, these findings should be interpreted as exploratory and require multicenter and longitudinal validation before clinical application.