Genetic Predisposition to Pancreatic Cancer: A Systematic Review of Hereditary Syndromes and Familial Aggregation.

Pancreatic cancer is a highly lethal malignancy, with a 5-year survival rate of approximately 8%. Roughly 10% of cases occur in individuals with familial pancreatic cancer or identified high-risk germline mutations, including STK11, CDKN2A, BRCA1/2, MLH1, and MSH2. We aimed to evaluate the risk of pancreatic cancer associated with inherited genetic mutations and to characterize these genetic syndromes. A systematic search of the PubMed database up to 2024 identified 1500 articles, of which 90 met the criteria for inclusion in this review. High-risk individuals were defined as those with at least a 10-fold increased risk, moderate risk as 5-10-fold and low risk as under 5-fold. High-risk individuals included those with Peutz-Jeghers syndrome (132-140-fold risk), hereditary pancreatitis (50-87-fold risk), Familial Atypical Multiple Mole Melanoma syndrome (up to 48-fold risk), hereditary breast and ovarian cancer with BRCA2 mutation (up to 22-fold risk), and familial pancreatic cancer with at least three affected relatives (up to 32-fold risk). Moderate-risk patients had BRCA1, MLH1, MSH2, MSH6, p53, and ATM mutations, as well as familial pancreatic cancer with 1-2 affected kindred. Low-risk patients had familial adenomatous polyposis. Identifying high-risk individuals is crucial for effective genetic counseling, testing, and potential screening programs to facilitate early diagnosis and improve outcomes. Future research should prioritize large prospective cohorts, screening programs, and the integration of emerging technologies, such as AI-assisted imaging.