Cross-Linked Multimeric Pro-Peptides of Type III Collagen (PC3X) in Hepatocellular Carcinoma - A Biomarker That Provides Additional Prognostic Value in AFP Positive Patients

Christina Jensen; Signe Holm Nielsen; Mohammed Eslam; Federica Genovese; Mette Juul Nielsen; Roslyn Vongsuvanh; Raj Uchila; David van der Poorten; Jacob George; Morten Asser Karsdal; Diana Julie Leeming; Nicholas Willumsen

doi:10.2147/JHC.S275008

Cross-Linked Multimeric Pro-Peptides of Type III Collagen (PC3X) in Hepatocellular Carcinoma - A Biomarker That Provides Additional Prognostic Value in AFP Positive Patients

J Hepatocell Carcinoma. 2020 Nov 9:7:301-313. doi: 10.2147/JHC.S275008. eCollection 2020.

Authors

Affiliations

¹ Biomarkers & Research, Nordic Bioscience, Herlev, Denmark.
² Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
³ Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark.
⁴ Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.

Abstract

Purpose: Non-invasive biomarkers for diagnosing and prognosing hepatocellular carcinoma (HCC) are urgently needed. Cirrhosis is present in 80-90% of HCC patients. Cirrhosis is characterized by deposition and cross-linking of collagens that have crucial roles in HCC initiation and progression. We evaluated circulating cross-linked pro-peptides of type III collagen (PC3X) as a diagnostic and prognostic biomarker for HCC.

Patients and methods: PC3X was measured by ELISA in plasma from patients with HCC (n=79), cirrhosis (n=86), non-cirrhotic hepatitis-B infection (n=74) and from healthy controls (n=44). PC3X was compared to the liver fibrosis marker PRO-C3 and the HCC tumor-cell derived marker alpha-fetoprotein (AFP). Diagnostic and prognostic potential was evaluated by AUROC and by calculating hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS).

Results: PC3X, PRO-C3 and AFP were significantly elevated in patients with HCC compared to other liver diseases and healthy controls (p=0.0002, p<0.0001). In patients with normal AFP (<20 IU/mL), PC3X and PRO-C3 separated HCC from cirrhosis with an AUROC of 0.72 and 0.68, respectively. High PC3X and AFP predicted for poor PFS (HR_PC3X=1.80, p=0.032; HR_AFP=1.70, p=0.031) and OS (HR_PC3X=2.12, p=0.024; HR_AFP=2.55; p=0.003), whereas PRO-C3 did not (PFS: HR=1.19, p=0.059 and OS: HR=1.12, p=0.324). PC3X was independent of AFP (PFS: HR=1.74, p=0.045 and OS: HR=2.21, p=0.018) and combining the two improved prognostic value (PFS: HR=2.66, p=0.004 and OS: HR=5.86, p<0.0001).

Conclusion: PC3X is associated with HCC independent of AFP and provides diagnostic and prognostic value for HCC patients. If validated, this suggests that PC3X has biomarker potential for HCC.

Keywords: extracellular matrix; fibrosis; liver cancer; tumor microenvironment.

Grants and funding

The ECM biomarker development and assessment were supported by the Danish Research Foundation. M. Eslam, D. v. Poorten and J. George are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206, APP1149976) and Project grants (APP1107178 and APP1108422).