Genetics of Paragangliomas (Pheochromocytomas)

Wan-Chen WuTaiwan Speaker Genetics of Paragangliomas (Pheochromocytomas)Background: Pheochromocytomas and paragangliomas (PPGLs) represent the most heritable human neoplasms, with nearly 80% of cases now attributable to either germline or somatic driver mutations. As we move into 2026, the paradigm of PPGL management has shifted from symptomatic treatment to genotype-driven precision care. This presentation integrates global molecular advancements with a specific focus on the unique genetic signatures identified within the Asia-Oceania region, particularly highlighting recent discoveries from the Taiwan research team. Molecular Classification and Pathway Signatures: Advanced multi-omics profiling has refined the classification of PPGLs into at least eight distinct molecular subtypes, primarily converging on three key signaling clusters: Pseudohypoxia (e.g., SDHx, VHL, FH), Kinase Signaling (e.g., RET, NF1, HRAS), and Wnt-Altered pathways (e.g., MAML3 fusions, CSDE1). Each cluster is characterized by a unique "molecular-clinical-biochemical-imaging" quadruple phenotype, which dictates tumor location, secretory profile, metastatic potential, and responsiveness to specific functional imaging modalities. The Asia-Oceania Perspective and the Taiwan Experience: Emerging data suggest significant ethnic variations in the genetic architecture of PPGLs. While Sino-Caucasian comparative studies have identified a higher prevalence of HRAS and FGFR1 mutations in Chinese cohorts, pioneering research from the National Taiwan University Hospital (NTUH) team has unveiled critical local nuances. A defining feature of the Taiwanese genetic landscape is the identification of a notable founder effect in the SDHD gene, which distinguishes local patients from other East Asian populations. These findings, alongside multicenter data from Korea, underscore the necessity of population-specific diagnostic algorithms in the Asia-Pacific region. Clinical Translation and Precision Management: The high prevalence of pathogenic variants -even in "apparently sporadic" or "incidental" presentations - mandates universal genetic testing for all PPGL patients. For those with initial negative results, longitudinal multigene panel retesting is essential as the list of susceptibility genes expands. Genotype-informed care now guides every facet of clinical practice, from personalized surveillance and the selection of functioning scan (such as 68Ga-DOTATATE PET/CT) to the application of targeted therapies (such as HIF-2α inhibitors). Conclusion: By bridging global molecular frameworks with localized research, such as the SDHD founder effect observed in Taiwan, we can achieve a higher standard of precision medicine. As we convene for AOCE 2026 in Taipei, these insights emphasize the importance of regional collaboration and the implementation of specific screening strategies to optimize the long-term outcomes for PPGL patients across Asia and beyond.