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

Abstract

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.

Paragangliomas of the Head and Neck: A Review of the Latest Diagnostic and Treatment Methods

“…The World Health Organization’s latest guidelines advise the use of SDHB immunohistochemistry in all head and neck paragangliomas, as it is the most frequent mutation associated with cases of metastatic paragangliomas [ 5 , 10 ]. Although SDHB is the most frequent mutation confirmed in metastases associated with head and neck paragangliomas, SDHD is the most commonly encountered mutation of all four, mostly discovered in benign forms [ 22 ]. SDHD mutations presence seems to be associated with a higher risk of occult paragangliomas, and it is frequently linked with paraganglioma syndrome 1, which consists of a concomitant identification of pheochromocytoma [ 10 , 15 , 23 ].…”

An evolving view of complex II—noncanonical complexes, megacomplexes, respiration, signaling, and beyond

“…Complex II activity has long been known as a tumor suppressor ( 124 ) but the mechanism underlying this phenomenon remains less clear. Confounding the understanding of this process is that mutations in different subunits may result in cells with different propensities to promote metastasis ( 125 , 126 ). Cancer cells disfavor oxidative phosphorylation and favor glycolysis, which is termed the Warburg effect, and complex II attenuates aerobic glycolysis.…”

Succinate dehydrogenase variants in paraganglioma: why are B subunit variants ‘bad’?

“…By this reasoning, it is not prognostically adequate to note only which is the variant subunit, but it is necessary to consider the biochemical impact of the particular inherited variant on SDH activity. A related hypothetical model has also recently been proposed ( Bayley & Devilee 2022 ).…”