Endoscopic liquid biopsies of gastric fluid in a large patient cohort reveal DNA content as a candidate tumor biomarker in gastric cancer

Abstract Background Human gastric cancer remains a diagnostic and therapeutic challenge worldwide. Improved prognostic biomarkers may support treatment planning, including surgery, neoadjuvant and adjuvant therapies. We offer a new liquid biopsy approach, integrated with esophagogastroduodenoscopy (EGD) to evaluate gastric fluid recovered from a large patient cohort (n=1,056 patients), demonstrating the value of a simple DNA concentration analysis to provide diagnostic support and prognosis in gastric cancer. Methods We performed an exploratory study to evaluate gastric fluid DNA (gfDNA) concentration in patients with normal gastric mucosa or diagnosed with peptic diseases, preneoplastic conditions, or cancer. Key variables including sex, gastric fluid pH, use of proton-pump inhibitors, tumor subtype, clinical stage, and disease outcomes were considered. Results gfDNA concentrations were significantly increased in gastric cancer versus all groups (mean 26.86 ng/µL; 95% CI: 20.05 to 33.79; p=3.61e-12) and as compared to non-malignant controls (normal mucosa and peptic diseases; mean 10.77 ng/µL; 95% CI: 9.23 to 12.33; p=9.55e-13), and preneoplastic conditions (mean 10.10 ng/µL; 95% CI: 7.59 to 12.60; p=1.10e-5). gfDNA concentrations were higher in advanced tumors (T3; mean 25.66 ng/µL; 95% CI: 19.46 to 31.85) compared to early-stage disease (T2 and below; mean 15.12 ng/µL; 95% CI: 9.73 to 20.50; p=5.97e-4). Our findings also suggest gfDNA prognostic value for gastric cancer diagnosed subjects. In this subset, patients with gfDNA concentrations >1.28 ng/µL showed longer progression-free survival (p=0.009), which correlated with increased tumor-infiltrating immune cells (p=0.001), remaining significant after adjusting for tumor stage (p=0.014). Conclusions While high gfDNA indicates gastric cancer in a general population and may contribute to disease management, its diagnostic clues should be integrated with further work up such as tissue biopsies, to ensure comprehensive and accurate clinical assessment. However, in patients with established gastric cancer, gfDNA is a potential prognostic marker, and subjects with high gfDNA content might paradoxically have better outcomes. The elevated presence of immune cell infiltrates—compared to those observed in peptic diseases and pre-neoplastic lesions (including their associated gastric cavity DNA shedding)—may serve as a critical missing link to resolve this empirical paradox.