Genetic Testing for Paraganglioma Patients
Primary Recommendation
All patients diagnosed with paraganglioma should be offered genetic testing regardless of age at presentation, family history, or whether the tumor appears sporadic. 1 This universal testing approach is justified because approximately 30-35% of all paragangliomas are hereditary, and even apparently sporadic cases harbor germline mutations in 5.6-14% of patients. 1, 2
Mandatory Core Gene Panel
DNA sequencing and deletion/duplication testing are obligatory for the following genes: 1
- SDHB - Critical due to high malignancy risk (30-40% metastatic potential) and aggressive behavior 1, 3
- SDHD - Accounts for 6.2% of all paragangliomas 1
- VHL - Associated with von Hippel-Lindau syndrome 1
- RET - Associated with MEN2 syndrome 1
- NF1 - If neurofibromatosis has not been ruled out clinically with rigorous skin examination 1
- FH - If hereditary leiomyomatosis syndrome not excluded clinically 1
- MEN1 - May be included, though paragangliomas are rare in this syndrome 1
Recommended Additional Genes
DNA sequencing (with deletion testing when appropriate) is recommended but not obligatory for: 1
- SDHA - Most commonly associated with gastric GISTs in SDH-related tumors 1
- SDHC - Accounts for 2% of all paragangliomas 1
- SDHAF2 - Rare but important for surveillance planning 1
- TMEM127 - Found in 0.6-2% of cases 1
- MAX - Found in 1.1% of cases 1
The rationale for these being "recommended but not obligatory" is limited knowledge on optimal surveillance protocols, not because they are less clinically relevant. 1
Critical Technical Requirements
Large deletion/duplication analysis is essential and must be included: 1
- Large deletions represent 11-19% of all pathogenic variants in SDHB, SDHC, and SDHD 1
- Up to 30% of VHL mutations are large deletions 1
- Standard sequencing alone will miss these mutations 4
- Multiplex PCR or similar techniques should be used to detect gross deletions 4
Sample Collection
DNA from peripheral blood is the recommended specimen for germline testing. 1 Tumor tissue analysis is not performed in routine clinical practice, though if a variant is detected in tumor tissue, targeted testing of peripheral blood is necessary to confirm it is germline rather than somatic. 1
Research-Only Genes
Testing for the following genes should only be performed in research settings due to insufficient data for surveillance programs: 1
- BAP1, EGLN1/PHD2, EGLN2/PHD1, EPAS1/HIF2A, KIF1B, KMT2D, MDH2 1
Modern Testing Approach
Next-generation sequencing (NGS) multigene panels are now the standard approach. 1, 5 Historical algorithms based on patient phenotype, hormone production, or tumor location have been abandoned due to the increased efficiency and lower cost of NGS. 1 NGS-based comprehensive testing shows 98.7% sensitivity and allows simultaneous analysis of all relevant genes. 5
Additional Considerations from ASCO Guidelines
Given the importance of BRCA1, BRCA2, and Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM), it is reasonable to include these genes in multigene panels for any patient with cancer undergoing germline genetic testing. 1 However, this is a general cancer testing recommendation rather than specific to paraganglioma management.
Clinical Pitfalls to Avoid
- Do not skip deletion/duplication testing - this will miss 11-30% of pathogenic variants depending on the gene 1
- Do not rely on family history - even "sporadic" cases have germline mutations in 5.6-14% of cases 1
- Do not use phenotype-based algorithms - these are outdated and miss hereditary cases 1
- Do not test tumor tissue alone - germline testing from blood is required to distinguish hereditary from somatic mutations 1
Why SDHB Testing is Critical
SDHB mutations warrant special emphasis because they are associated with significantly higher risk of metastatic disease (30-40%), aggressive tumor behavior, and death. 3, 2 Patients with SDHB mutations require lifelong surveillance due to this elevated malignancy risk. 2, 6