Speakers - DEWC2025

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst survival outcomes reflecting a lack of effective strategies for early detection. The majority of PDAC patients have locally advanced disease or distant metastasis at presentation offering few opportunities for effective clinical intervention. Improvement in survival rates depends on innovative early detection approaches and novel treatment strategies. Recently published polygenic risk scores (PRS) utilize common genetic variants associated with PDAC risk. We compared the performance of these PRS in an independent cohort to determine their utility for identifying individuals at risk of PDAC. We also evaluated how risk is modified in the presence of long standing and recent diabetes mellitus (DM).

We considered cases and matched cancer-free controls drawn from the UK Biobank and a combined PRS model using single nucleotide polymorphisms (SNPs) associated with PDAC. The PRS was adjusted for ancestry, smoking, DM, waist circumference, and family history of digestive cancer. The combined PRS achieves an area under the curve (AUC) value of 0.605, and significantly improves the overall clinical risk model (AUC = 0.83; P = .0002). Individuals in the fifth quintile have a 2.74-fold increased risk of developing PDAC versus those in the first quintile (P < .001) and have a 3.05-fold increased risk of developing PDAC if they have DM versus those without DM (P < .001). The positive predictive value is 11.9% in participants without DM, 23.9% with long-standing DM, and 86.7% with recent onset DM. Our ongoing work to improve the predictive utility of PRS-based models for PDAC will be discussed.