Serological detection of Type XVII collagen shedding suggests prognostic relevance in esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is an aggressive malignancy with poor prognosis and rising incidence in Western countries. Identifying reliable, non-invasive biomarkers for prognostic stratification and disease monitoring remains a clinical challenge. Type XVII collagen is a transmembrane protein mediating epithelial-basement membrane adhesion. Its aberrant expression and ectodomain shedding have been linked to epithelial damage and tumor progression. Interestingly, COL17A1 has been reported to be downregulated in EAC compared to Barrett's esophagus and healthy tissue, suggesting loss of epithelial integrity during malignant transformation. In this study, we evaluated the serological biomarker potential of PRO-C17, which quantifies the shed ectodomain of type XVII collagen, in two independent cohorts of treatment-naïve EAC patients. PRO-C17 levels were measured by competitive ELISA in EDTA plasma from 57 treatment-naïve EAC patients (Cohort I, Karolinska University Hospital). A second cohort (Cohort II, University of Leipzig) included 64 serum samples from treatment-naïve EAC patients. All samples were collected at diagnostic endoscopy prior to oncologic treatment. For both cohorts, 20 healthy controls were included, matched for sample matrix, age, and gender. Prognostic associations with overall survival (OS) were assessed in resectable patients (n=54 in Cohort I; n=44 in Cohort II) using Kaplan-Meier and multivariate Cox models. Cohort-specific median PRO-C17 levels were used as cut-offs. In Cohort I, PRO-C17 levels were significantly lower in EAC patients compared to controls (p<0.001); in Cohort II, no significant difference was observed, though a similar trend was noted. In both cohorts, high baseline PRO-C17 levels were independently associated with poorer OS (Cohort I: p=0.01, HR=2.63, 95% CI: 1.20-5.56; Cohort II: p=0.013, HR=2.85, 95% CI: 1.22-6.71). Among early-stage patients, elevated PRO-C17 identified individuals with significantly worse OS, suggesting that PRO-C17 may reflect tumor aggressiveness even in clinically early-stage disease. No significant differences were seen in late-stage subgroups. In Cohort II, lower baseline PRO-C17 was also associated with better tumor regression grades (TRG), suggesting potential predictive value for treatment response. PRO-C17 shows consistent prognostic value across two independent EAC cohorts with different sample matrices. Elevated levels were associated with poorer OS, particularly in early-stage disease, supporting its use as a non-invasive biomarker for risk stratification. Increased ectodomain shedding may reflect tumor aggressiveness, while the overall lower PRO-C17 levels in EAC vs. healthy controls may reflect COL17A1 downregulation during tumor progression. These findings support prospective validation of PRO-C17 as a clinically relevant biomarker in EAC.