Identification of serum protein biomarkers for pre‐cancerous lesions associated with pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis as early-stage asymptomaticity leads to late-stage diagnoses. Strategies to detect PDAC earlier or identify high-risk individuals are therefore paramount. Here, we report results from genetically engineered mice and PDAC patients that identify serum proteins associated with pancreatic intraepithelial neoplasms (PanINs), the most common PDAC precursor, and early-stage PDAC. Initially, we screened previously described PanIN-abundant mice, harbouring pancreatic and duodenal homeobox 1 (Pdx1)-Cre, Lox-STOP-Lox-Kras^G12D/+ and floxed alleles of essential autophagy genes autophagy-related 7 (Atg7) or autophagy-related 5 (Atg5). Sera from these mice were assessed by proteomics and hits were compared to those in Lox-STOP-Lox-Kras^G12D/+ Lox-STOP-Lox-Trp53^R172H/+ Pdx1-Cre (KPC) mice, which closely recapitulate human disease, and early-stage (I-II) PDAC patients. Levels of inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) were significantly elevated in all three screens, with complement C5, complement factors B and H (CFB/CFH), and monocyte differentiation antigen CD14 increased in KPC mice and PDAC patients; and all were significantly increased co-ordinately in PDAC according to disease stage. Serum levels of C5, CFH and CD14 together constitute a novel panel for identifying PanINs and early-stage PDAC with confidence, and when combined with additional screening, could help increase survival from this dismal disease.