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

## TL;DR

This paper reviews how inherited genetic mutations and family history increase the risk of pancreatic cancer, emphasizing the importance of early detection and genetic counseling for high-risk individuals.

## Contribution

The paper systematically evaluates the risk levels associated with specific hereditary syndromes and mutations in pancreatic cancer, providing updated risk stratification for clinical management.

## Key findings

- High-risk individuals have up to 140-fold increased risk of pancreatic cancer, including those with Peutz–Jeghers syndrome and hereditary pancreatitis.
- BRCA2 mutations are associated with up to 22-fold increased risk, while familial pancreatic cancer with three affected relatives has up to 32-fold risk.
- Moderate and low-risk categories include mutations in BRCA1, MLH1, MSH2, and familial adenomatous polyposis.

## Abstract

Pancreatic cancer has a high mortality rate despite its low incidence. Of all cases, approximately 10% are linked to inherited genetic mutations or familial clusters. High-risk individuals are those with Peutz–Jeghers syndrome, hereditary pancreatitis, Familial Atypical Multiple Mole Melanoma syndrome, hereditary breast and ovarian cancer with BRCA2 mutation and clusters of familial pancreatic cancer with at least three affected kindreds. Early detection through targeted screening in these patients may improve the outcomes. Genetic counseling and multigene testing are essential for risk stratification and management.

Background: 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. Aim: We aimed to evaluate the risk of pancreatic cancer associated with inherited genetic mutations and to characterize these genetic syndromes. Methods: A systematic search of the PubMed database up to 2024 identified 1500 articles, of which 90 met the criteria for inclusion in this review. Results: 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. Conclusions: 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.