Multi-omic analysis of SDHB-deficient pheochromocytomas and paragangliomas identifies metastasis and treatment-related molecular profiles.

Summary

Across 94 SDHB-mutant PCPG, sympathetic vs parasympathetic tumors show distinct cell-of-origin molecular programs. TERT and ATRX alterations mark metastatic disease with increased mutation load and telomeric/transcriptional features. Two acquired resistance mechanisms to alkylating chemotherapy were identified: MGMT overexpression and mismatch repair deficiency with hypermutation.

Key Findings

• Sympathetic vs parasympathetic SDHB-mutant PCPG show distinct molecular profiles reflecting cell-of-origin.
• TERT and ATRX alterations are associated with metastatic PCPG, with higher mutation loads and specific telomeric/transcriptional signatures.
• Most tumors have quiet genomes with occasional cooperative drivers (e.g., EPAS1/HIF-2α).
• Two resistance mechanisms to alkylating chemotherapy were identified: MGMT overexpression and mismatch repair deficiency causing hypermutation.

Clinical Implications

Support routine testing of TERT/ATRX in SDHB-mutant PCPG to stratify metastasis risk; consider MGMT expression and MMR status when selecting alkylating agents or immunotherapy, and for clinical trial eligibility.

Limitations

• Observational design; lacks prospective clinical validation of biomarker-guided decisions.
• Sample size is substantial for a rare tumor but still limits subgroup analyses.

Future Directions

Prospectively validate TERT/ATRX, MGMT, and MMR status as predictive/prognostic markers; explore tailored regimens (e.g., MGMT-low alkylator sensitivity, MMR-deficient immunotherapy) and integrate multi-omic signatures into risk models.