We explored the ability of DNA methylation of PI3K-related genes to differentiate between malignant and healthy pancreatic tissue using distinct pancreatic cancer cohorts, and found that the methylation levels of the ITGA4, SFN, ITGA2, and PIK3R1 genes are altered in tumour samples since the early stages of malignant transformation and could serve as new diagnostic tools. Here, SFN is linked to familial pancreatic carcinoma.