Identification of novel plasma proteins as promising noninvasive biomarker for early diagnosis and surveillance of pancreatic ductal adenocarcinoma.

Abstract

Background: Although cancer antigen 19-9 (CA 19-9) is the only FDA-approved biomarker for pancreatic ductal adenocarcinoma (PDAC), its diagnostic effectiveness is limited, as it may not be elevated in 15-25% of patients. This study aims to explore novel plasma proteins associated with PDAC as potential biomarkers for early diagnosis and clinical surveillance.

Methods: Novel plasma protein biomarkers potentially causally associated with PDAC were identified using Mendelian randomization (MR). These biomarkers were validated in a multicenter study encompassing 230 tissue and 1,011 plasma samples to establish a diagnostic model for PDAC. Furthermore, their pre- and post-operative levels were compared to evaluate their potential as clinical surveillance biomarkers.

Results: Genetically predicted expression of seven proteins potentially causally associated with an increased risk of PDAC. In a multicenter, large-scale study, Keratin 5 (KRT5) and Versican (VCAN) were identified as promising biomarkers for PDAC, with an area under the curve (AUC) of 0.90, and a combined panel including CA 19-9 achieved an AUC of 0.95. Additionally, plasma KRT5 and VCAN demonstrated superior diagnostic performance for early-stage PDAC with CA 19-9 levels below 37 U/mL (Stage I, AUC 0.85; Stage II, AUC 0.85). The specificity of plasma KRT5 and VCAN for PDAC was further validated by comparing their expression levels across various digestive cancers. Moreover, a significant decrease in plasma KRT5 and VCAN levels was observed post-surgery (P < 0.05), supporting their potential as biomarkers for clinical surveillance of PDAC.

Conclusions: Plasma KRT5 and VCAN proteins may serve as promising valuable biomarkers for the early diagnosis and clinical surveillance of PDAC.