Unveiling Circulating Targets in Pancreatic Cancer: Insights from Proteogenomic Evidence and Clinical Cohorts

Abstract

Pancreatic cancer (PC), lacking biomarkers and effective therapeutics, remains highly lethal. Data regarding the correlations of PC risk and the individual plasma proteome known for minimally cancer biomarkers, are scarce. Here, we measure 1,345 human plasma proteins via Proteome-Wide Association Studies, presenting 78 proteins are prominently related to PC risk, including 4 proteins (ROR1, FN1, APOA5, ABO) exhibit the strongest causal association identified via Mendelian Randomization and Colocalization. Our two independent cohorts further demonstrate FN1 and ABO are highly expressed in blood or tumors from patients with PC compared to specimens from healthy individuals or para-tumors. Moreover, patients with higher levels of FN1 and ABO in their blood or tumors have worse median survival than those with lower levels. Multiple drugs targeting FN1 are currently available or undergoing clinical testing, making FN1 a promisingly repurposed therapeutic target in addition to severing as a circulating prognostic indicator for PC.