Molecular clusters and precision medicine in pheochromocytomas and paragangliomas

SDHB

Three molecular clusters: pseudohypoxic, driven by Krebs cycle alterations (SDHx, FH, MDH2, DLST) and HIF-2α pathway alterations (VHL, EPAS1, EGLN1/EGLN2); kinase signalling, driven by RAS/MAPK and PI3K/AKT activation (RET, NF1, HRAS, TMEM127, MAX); and Wnt signalling, characterised mainly by MAML3 fusions.

This review summarises the genomic characterisation of pheochromocytomas and paragangliomas, rare neuroendocrine tumours derived from chromaffin cells. Up to 40% harbour a germline pathogenic variant, the highest proportion among human neoplasms, with somatic driver events identified in a substantial fraction of the remainder. Integrative multi-omic studies have established three molecular clusters — pseudohypoxic, kinase signalling and Wnt signalling — and the authors use EPAS1/HIF-2α and RET as examples of how germline, somatic, mosaic and fusion events converge on shared pathways targetable with approved inhibitors (belzutifan for HIF-2α, selpercatinib and pralsetinib for RET). The review also covers genomic determinants of metastatic risk (SDHB, ATRX, TERT, MAML3 fusions), the immune microenvironment of metastatic disease and emerging theranostic approaches.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The proposed framework is useful in the cancer genetics clinic because it links a single signalling pathway to heterogeneous mechanisms of involvement: a germline RET patient, a somatic event and a fusion may fall under the same therapeutic logic, which gene-by-gene reading does not reveal. The 40% germline proportion alone justifies systematic testing in any pheochromocytoma or paraganglioma, an indication already established but unevenly applied outside specialist centres. The review remains a synthesis and provides neither surveillance algorithm nor decision threshold — the link between molecular cluster and follow-up interval remains to be formally established.

Analysis by Dr Thibaut Benquey