Hypothesis: Why Different Types of SDH Gene Variants Cause Divergent Tumor Phenotypes.

Despite two decades of paraganglioma-pheochromocytoma research, the fundamental question of how the different succinate dehydrogenase (SDH)-related tumor phenotypes are initiated has remained unanswered. Here, we discuss two possible scenarios by which missense (hypomorphic alleles) or truncating (null alleles) SDH gene variants determine clinical phenotype. Dysfunctional SDH is a major source of reactive oxygen species (ROS) but ROS are inhibited by rising succinate levels. In scenario 1, we propose that SDH missense variants disrupt electron flow, causing elevated ROS levels that are toxic in sympathetic PPGL precursor cells but well controlled in oxygen-sensing parasympathetic paraganglion cells. We also suggest that SDHAF2 variants, solely associated with HNPGL, may cause the reversal of succinate dehydrogenase to fumarate reductase, producing very high ROS levels. In scenario 2, we propose a modified succinate threshold model of tumor initiation. Truncating SDH variants cause high succinate accumulation and likely initiate tumorigenesis via disruption of 2-oxoglutarate-dependent enzymes in both PPGL and HNPGL precursor tissues. We propose that missense variants (including SDHAF2) cause lower succinate accumulation and thus initiate tumorigenesis only in very metabolically active tissues such as parasympathetic paraganglia, which naturally show very high levels of succinate.