Pancreatitis, whether acute or chronic, can increase the risk of pancreatic cancer over time. Chronic inflammation can promote cell proliferation, cause DNA damage, and induce angiogenesis, creating a microenvironment conducive to cancer development. While environmental and lifestyle factors like smoking, alcohol consumption, and obesity obviously play a significant role in disease susceptibility, genetic predisposition is a key factor in the progression from pancreatitis to pancreatic cancer.
Among the most well-known genetic risk factors for pancreatic cancer are germline mutations in the BRCA1, BRCA2, and NOD2 genes. BRCA1 and BRCA2 mutations, which are typically associated with hereditary breast and ovarian cancer syndromes, are also found in a subset of pancreatic cancer cases. NOD2, a gene involved in immune regulation, has been implicated in inflammatory diseases and pancreatitis, with certain genetic variants significantly increasing cancer risk.
How Does Pancreatitis Lead to Pancreatic Cancer?
- Chronic Inflammation: Repeated episodes of inflammation lead to sustained tissue damage and repair, increasing the likelihood of genetic mutations.
- DNA Damage: Pancreatic cells exposed to prolonged inflammation undergo genetic instability, predisposing them to tumorigenesis.
- Angiogenesis and Fibrosis: The formation of new blood vessels and excessive scarring create an environment that supports cancer cell growth.
The Role of BRCA1 and BRCA2 in Pancreatic Cancer
BRCA1 and BRCA2 are tumour suppressor genes that play essential roles in DNA repair through homologous recombination. Mutations in these genes compromise the ability of cells to repair DNA damage, increasing the risk of cancer development.
BRCA1 Mutations and Pancreatic Cancer Risk
BRCA1 mutations are found in approximately 4–7% of pancreatic cancer cases. Individuals with BRCA1 mutations have an increased susceptibility to various cancers, including breast, ovarian, and pancreatic cancer.
- BRCA1-related pancreatic cancers often exhibit aggressive tumour behaviour and poor prognosis.
- Patients with a family history of BRCA1-associated cancers should consider genetic screening.
- Carriers of BRCA1 mutations may benefit from PARP inhibitors, which target cancer cells with defective DNA repair mechanisms.
BRCA2 Mutations: The More Common Genetic Risk Factor
BRCA2 mutations are found in 5–17% of pancreatic cancer cases and increase the risk of disease by 3.5 to 10 times.
- BRCA2 mutations are more frequently associated with familial pancreatic cancer.
- BRCA2-related tumours may respond to platinum-based chemotherapy and PARP inhibitors.
- Genetic testing for BRCA2 mutations is recommended for high-risk individuals, especially those with a family history of pancreatic, breast, or ovarian cancer.
NOD2 rs2066847 Variant and Increased Cancer Risk
A new 2025 study by Matykiewicz et al*., identified the NOD2 rs2066847 polymorphism as a significant genetic risk factor for pancreatic cancer.
- Patients with the rs2066847 variant had a threefold increased risk of pancreatic cancer.
- This SNP is associated with chronic inflammatory conditions, which may create a cancer-promoting environment in the pancreas.
- Understanding the link between NOD2 mutations and pancreatic cancer could lead to new diagnostic and therapeutic strategies.
* https://pubmed.ncbi.nlm.nih.gov/39805914/
Genetic Testing and Risk Assessment for Pancreatic Cancer
With the growing understanding of genetic risk factors, genetic testing has become an essential tool for early detection and risk management in pancreatic cancer. Identifying high-risk individuals before cancer develops allows for preventative strategies and targeted therapies.
Who Should Consider Genetic Testing?
Genetic testing for BRCA1, BRCA2, and NOD2 mutations is recommended for individuals who:
- Have a family history of pancreatic, breast, ovarian, or prostate cancer.
- Have been diagnosed with pancreatitis without a clear environmental cause.
- Are of Ashkenazi Jewish descent, as they have a higher prevalence ofBRCA mutations. (1 in 40 Ashkenazi Jews has a faulty BRCA gene, compared to around 1 in 250 individuals in the UK general population).
- Have multiple relatives affected by hereditary cancers.
Potential for Targeted Therapies and Precision Medicine
The identification of BRCA1, BRCA2, and NOD2 mutations in pancreatic cancer has led to significant advances in personalised medicine, where treatment is tailored based on an individual’s genetic profile.
PARP Inhibitors for BRCA-Mutated Pancreatic Cancer
Poly (ADP-ribose) polymerase (PARP) inhibitors are a promising class of drugs that target tumours with defective DNA repair mechanisms, such as those with BRCA1/2 mutations.
- Olaparib (Lynparza) has shown prolonged survival benefits in BRCA-mutated pancreatic cancer patients.
- Platinum-based chemotherapy (such as cisplatin or oxaliplatin) is also more effective in BRCA-mutated cancers due to their reliance on DNA repair pathways.
- Patients with BRCA mutations may benefit from clinical trials investigating new targeted therapies.
Immunotherapy Strategies for NOD2-Related Pancreatic Cancer
Given that NOD2 plays a role in immune regulation, researchers are exploring immunotherapy approaches for pancreatic cancer patients with NOD2 mutations.
- Checkpoint inhibitors (such as PD-1/PD-L1 blockers) could help the immune system recognise and attack cancer cells in genetically susceptible individuals.
- Inflammation-targeting drugs could reduce the chronic inflammatory environment that drives cancer progression in NOD2-mutated patients.
In Conclusion
Pancreatic cancer is a highly aggressive disease with limited treatment options, making early detection and risk assessment vital. While environmental factors like smoking, alcohol consumption, and obesity contribute to the disease, genetic mutations in BRCA1, BRCA2, and NOD2 significantly increase susceptibility.
By integrating genetic screening, lifestyle modifications, and emerging therapies, we can improve early detection, prevention, and treatment strategies for individuals at risk of pancreatic cancer.
