Pancreatic cancer (PC) has the lowest survival rate of all cancers in Europe, with no early detection strategies available. First-degree relatives of patients with PC have at least a 2-fold increased risk of developing the disease, although it is well-known that besides family history, also older age, tobacco, alcohol abuse and other epidemiological risk factors predispose to PC onset. Even in families with high genetic predisposition to PC, existing cancer predictive Machine Learning models are of very limited use, since their predictive accuracy is generally low. Epigenetic biomarkers are not a part of existing risk indexes yet, although strong evidence shows that methylation patterns in blood can efficiently predict cancer mortality and that liquid biopsy has a potential to revolutionise early cancer diagnostics. The IMAGene project will develop, calibrate and test a comprehensive Cancer Risk Prediction Algorithm (CRPA) to predict PC in high-risk (HR) asymptomatic subjects, by including omics, imaging, epidemiologic, lifestyle and psychological data records. IMAGene will also investigate the potential for DNA methylation biomarkers to improve currently available risk indexes, and validate the feasibility of using liquid biopsies for early detection of cancer in HR individuals. A detailed ethical and cost-utility analysis will respectively guide a responsible application of the procedures and will balance benefits and impact for the health care system in four EU countries.