Can pancreatic cancer be hereditary?

Pancreatic Cancer Can Run in Families

Yes, pancreatic cancer can definitely run in families, with approximately 10% of pancreatic cancer cases having a familial component. 1 This familial clustering occurs through both known genetic syndromes and familial pancreatic cancer (FPC), which has specific diagnostic criteria.

Familial Risk Patterns

The risk of developing pancreatic cancer increases significantly with family history:

• Having 1 first-degree relative with pancreatic cancer increases risk 4.6-fold 1
• Having 2 first-degree relatives increases risk 6.4-fold 1
• Family history of early-onset pancreatic cancer (diagnosed before age 50) is associated with even higher risk (standardized incidence ratio: 9.31) 1
• Lifetime risk increases as the age of onset in affected family members decreases 1

Defining Familial Pancreatic Cancer

Familial pancreatic cancer is specifically defined as:

• Having at least 2 first-degree relatives with pancreatic cancer 1
• Not part of a known cancer syndrome 2

This definition helps identify high-risk individuals who should be considered for genetic testing and potentially surveillance.

Genetic Basis

The genetic basis for familial pancreatic cancer is complex:

• In approximately 80% of patients with family history of pancreatic cancer, no known genetic cause is identified 1
• In the remaining 20%, several genes have been implicated:
  • Most common pathogenic germline alterations: BRCA1, BRCA2, ATM, PALB2, MLH1, MSH2, MSH6, PMS2, CDKN2A, and TP53 1
  • A retrospective review found genetic mutations in 28% of families with history of pancreatic cancer 1

Associated Hereditary Syndromes

Several hereditary syndromes increase pancreatic cancer risk:

1. Peutz-Jeghers syndrome (STK11 gene mutations): Up to 132-fold increased risk 1
2. Familial pancreatitis: 26-fold to 87-fold increased risk 1
3. Hereditary breast-ovarian cancer syndrome (BRCA1/2 mutations) 3
4. Hereditary nonpolyposis colorectal cancer (Lynch syndrome) 3
5. Familial atypical multiple-mole melanoma (p16/CDKN2A mutations) 3

Clinical Implications and Management

For individuals with suspected familial risk:

1. Genetic risk evaluation should be conducted with healthcare providers familiar with hereditary cancer syndromes 1

2. Candidates for genetic testing:

   • All patients diagnosed with pancreatic adenocarcinoma 1
   • Individuals with family history meeting criteria for familial pancreatic cancer 1
   • Individuals with three or more pancreatic cancer cases on the same side of the family 1
   • Individuals meeting criteria for hereditary syndromes associated with pancreatic cancer 1

3. Genetic testing approach:

   • Ideally performed in affected family members first 1
   • Should use multigene panels that include all genes associated with pancreatic cancer risk 1
   • Should be performed early in the disease course for patients with pancreatic cancer 1

4. Risk-reducing strategies for high-risk individuals:

   • Smoking cessation and weight management 1
   • Consideration of pancreatic cancer surveillance in specialized centers 1

Important Caveats

• Even with a strong family history, genetic testing does not detect a pathogenic mutation in 90% of families meeting criteria for familial pancreatic cancer 1
• Family history assessment should include first and second-degree relatives, with attention to age at diagnosis 1
• Ashkenazi Jewish ancestry is associated with higher risk of familial pancreatic cancer 4
• Some patients with germline mutations lack the typical family history patterns associated with hereditary syndromes 1

Understanding the familial component of pancreatic cancer is crucial for identifying high-risk individuals who may benefit from genetic counseling, testing, and potentially surveillance for early detection.