Noninvasive prognostic biomarker potential of quantifying the propeptides of Type XI collagen alpha-1 chain (PRO-C11) in patients with pancreatic ductal adenocarcinoma

Neel Ingemann Nissen, Stephanie Kehlet, Astrid Z Johansen, Inna M Chen, Morten Karsdal, Julia S Johansen, Hadi M H Diab, Lars N Jørgensen, Shu Sun, Tina Manon-Jensen, Yi He, Lasse Langholm, Nicholas Willumsen, Neel Ingemann Nissen, Stephanie Kehlet, Astrid Z Johansen, Inna M Chen, Morten Karsdal, Julia S Johansen, Hadi M H Diab, Lars N Jørgensen, Shu Sun, Tina Manon-Jensen, Yi He, Lasse Langholm, Nicholas Willumsen

Abstract

Type XI collagen has been associated with tumor fibrosis and aggressiveness in patients with pancreatic ductal adenocarcinoma (PDAC). The propeptide on Type XI collagen is released into the circulation after proteolytic processing at either amino acid 253 or 511. This allows for a noninvasive biomarker approach to quantify Type XI collagen production. We developed two ELISA-based biomarkers, targeting the two enzymatic cleavage sites (PRO-C11-253 and PRO-C11-511). In a discovery cohort including serum from patients with PDAC (n = 39, Stages 1-4), chronic pancreatitis (CP, n = 12) and healthy controls (n = 20), PRO-C11-511, but not PRO-C11-253, was significantly upregulated in patients with PDAC and CP compared to healthy controls. Furthermore, PRO-C11-511 levels >75th percentile were associated with poor overall survival (OS) (HR, 95% CI: 3.40, 1.48-7.83). The PRO-C11-511 biomarker potential was validated in serum from 686 patients with PDAC. Again, high levels of PRO-C11-511 (>75th percentile) were associated with poor OS (HR, 95% CI: 1.68, 1.40-2.02). Furthermore, PRO-C11-511 remained significant after adjusting for clinical risk factors (HR, 95% CI: 1.50, 1.22-1.86). In conclusion, quantifying serum levels of Type XI collagen with PRO-C11-511 predicts poor OS in patients with PDAC. This supports that Type XI collagen is important for PDAC biology and that PRO-C11-511 has prognostic noninvasive biomarker potential for patients with PDAC.

Trial registration: ClinicalTrials.gov NCT03311776.

Keywords: biomarkers; collagen; extracellular matrix; pancreatic ductal carcinoma; tumor fibrosis.

© 2021 UICC.

References

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