Can family members get tested for Pancreatic Neuroendocrine Tumors (PNET)?

Genetic Testing for Family Members of Patients with Pancreatic Neuroendocrine Tumors (PNETs)

Yes, family members of patients with pancreatic neuroendocrine tumors (PNETs) should undergo genetic testing, particularly when there is a known hereditary syndrome or pathogenic variant identified in the affected family member. Genetic testing is crucial for early detection and management of potential disease in at-risk relatives.

When Genetic Testing is Recommended for Family Members

For Syndromic PNETs:

• First-degree relatives of patients with PNETs associated with known hereditary syndromes should be offered genetic testing for the specific pathogenic variant identified in the affected family member 1, 2
• Testing should focus on genes associated with hereditary syndromes that increase PNET risk:
  • Multiple Endocrine Neoplasia type 1 (MEN1)
  • Von Hippel-Lindau (VHL)
  • Neurofibromatosis type 1 (NF1)
  • Multiple Endocrine Neoplasia type 4 (MEN4)
  • Tuberous Sclerosis Complex (TSC)

For Non-Syndromic PNETs:

• First-degree relatives of patients with PNETs should be considered for genetic testing when:
  • The patient has multiple family members with PNETs or other endocrine tumors
  • The patient developed PNET at a young age (under 40)
  • The patient has multiple primary tumors

Specific Testing Recommendations by Syndrome

MEN1 Testing:

• Comprehensive MEN1 genetic testing is indicated for 1:
  • First-degree relatives of individuals with confirmed MEN1 pathogenic variants
  • Individuals with one MEN1-related tumor and a first-degree relative with MEN1
  • Anyone under age 30 with parathyroid hyperplasia, pancreatic islet tumors, or pancreatic precursor lesions

Other Syndromes:

• For families with identified pathogenic variants in other genes (CDKN2A, STK11, etc.), testing should be offered to first-degree relatives 2
• Testing should be performed using multigene panels that include all genes associated with PNET risk 1

Testing Process

Optimal Testing Approach:

1. Test affected individuals first - Whenever possible, genetic testing should begin with the family member diagnosed with PNET 1
2. Use targeted testing for relatives - Once a pathogenic variant is identified, relatives should be tested specifically for that variant 1
3. Early testing is preferred - Testing should be performed early in the disease course for patients with PNET, as mortality rates are high and the option to test the patient may not be available for long 1

When Affected Family Members Are Not Available:

• Testing may be performed in unaffected individuals following genetic risk assessment
• However, a negative test result in an unaffected individual without a known family mutation is considered clinically uninformative 1

Surveillance Recommendations for Mutation Carriers

For individuals identified with pathogenic variants, surveillance should begin at specific ages based on the gene involved:

• MEN1 mutation carriers: Begin annual biochemical screening at age 5 (prolactin) and age 10 (calcium) 1
• CDKN2A mutation carriers: Begin pancreatic screening at age 40 or 10 years younger than the earliest pancreatic cancer diagnosis in the family 1, 2
• STK11 mutation carriers: Begin screening at age 30-35 or 10 years younger than the earliest pancreatic cancer diagnosis in the family 1, 2
• BRCA1/2, ATM, PALB2 carriers: Begin screening at age 50 or 10 years younger than the earliest pancreatic cancer diagnosis in the family (only if there is additional family history of pancreatic cancer) 1, 2

Surveillance Methods

• Surveillance should be performed with contrast-enhanced MRI/MRCP and/or endoscopic ultrasound 1
• Screening at high-volume centers of expertise and in the context of research studies is preferred 1

Important Considerations

• The discovery of a familial genetic factor should be available in depersonalized form to inform the testing and clinical care of family members 3
• The possibility of such use should be made clear at the time of initial testing 3
• Even with strong family history, genetic testing does not detect pathogenic mutations in approximately 90% of families meeting criteria for familial pancreatic cancer 2

By identifying at-risk family members through genetic testing, appropriate surveillance can be implemented to detect tumors at earlier, more treatable stages, potentially reducing morbidity and mortality associated with PNETs.