A review of the tumour spectrum of germline succinate dehydrogenase gene mutations: Beyond phaeochromocytoma and paraganglioma

Abstract

The citric acid cycle, also known as the Krebs cycle, plays an integral role in cellular metabolism and aerobic respiration. Mutations in genes encoding the citric acid cycle enzymes succinate dehydrogenase, fumarate hydratase and malate dehydrogenase all predispose to hereditary tumour syndromes. The succinate dehydrogenase enzyme complex (SDH) couples the oxidation of succinate to fumarate in the citric acid cycle and the reduction of ubiquinone to ubiquinol in the electron transport chain. A loss of function in the succinate dehydrogenase (SDH) enzyme complex is most commonly caused by an inherited mutation in one of the four SDHx genes (SDHA, SDHB, SDHC and SDHD). This mechanism was first implicated in familial phaeochromocytoma and paraganglioma. However, over the past two decades the spectrum of tumours associated with SDH deficiency has been extended to include gastrointestinal stromal tumours (GIST), renal cell carcinoma (RCC) and pituitary adenomas. The aim of this review is to describe the extended tumour spectrum associated with SDHx gene mutations and to consider how functional tests may help to establish the role of SDHx mutations in new or unexpected tumour phenotypes.

Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker

“…Alternatively, succinate may be derived from glutamine-dependent anaplerosis, which was reported to be the main source of succinate in activated tumor-associated macrophages [ 26 ]. The increase in succinate in tumors has also been previously related to SDH dysfunction, such as papillary thyroid cancinoma, thyroid C-cell hyperplasia, pancreatic neuroendocrine tumors, paragangliomas, ovarian cancer, hepatocellular carcinoma, colorectal cancer, renal carcinomas and pituitary adenomas, among others [ 27 , 28 ]. There is, however, no evidence to show that SDH is dysfunctional in HNSCC and further studies are warranted to elucidate the precise mechanism underlying succinate accumulation and secretion in this cancer.…”

The Metabolic Fates of Pyruvate in Normal and Neoplastic Cells

“…Cardaci et al [ 171 ] studied the fates of pyruvate and oxaloacetate in non-transformed murine kidney cells lacking SDHB, one of the four subunits of succinate dehydrogenase (SDH), otherwise known as ETC Complex II. Mutations in SDH subunits, particularlly SDHB, occur in familial pheochromocytoma, paraganglioneuroma and other rare neoplasms leading to succinate accumulation and fumarate depletion [ 196 , 197 , 198 , 199 , 200 ]. This activates hypoxia- inducible factors, which inhibit α-ketoglutarate-dependent histone and DNA demethylases and promote global pseudo-hypoxia and hypermethylation that drive transformation [ 201 , 202 , 203 ].…”

The genetic basis of isolated mitochondrial complex II deficiency

“…Multiple pathomechanisms link SDHx variants and tumorigenesis, including increased ROS production, defective apoptosis and the abnormal stabilization of hypoxia-inducible factors (HIF), all of which fit with established models of tumorigenesis [ 15 ]. Pathogenic variants in SDHB and SDHC in particular, have been associated with the development of paragangliomas (PGLs) and pheochromocytomas (PHEOs); these are usually benign catecholamine-secreting tumours that are derived from the chromaffin cells of the adrenal medulla in the case of PGL, and the extra adrenal ganglia in the case of PHEOs [ 16 ].…”

“…Although approximately 75% of incidences of PGL/PCC remain localised and do not metastasize, they remain a cause of mortality and morbidity consequent to hypertension from uncontrolled catecholamine production and secretion. The association between SDHx defects and tumour development is not limited to PGL and PHEOs, but extends to other solid tissue tumours including gastrointestinal stromal tumours (GISTs), pituitary adenomas and renal cell carcinomas [ 15 ]. Where there is a hereditary component, patients are typically found to have inherited a single heterozygous pathogenic variant through the germline; in accordance with Knudson's theory, the second pathogenic ‘hit’ occurs as a random mutational event over the individual's lifetime and results in bi-allelic inactivation of SDH in that cell which evolves into a tumour through clonal expansion [ 17 ].…”

“…Despite this, clinical guidelines recommend surveillance of these at risk individuals to facilitate early detection of any abnormalities [ 19 ]. The remaining part of this review will focus on primary mitochondrial disease presentations associated with complex II dysfunction; the current knowledge of the link between complex II defects and cancer has been comprehensively reviewed elsewhere [ 15 ].…”