These results identify HLRCC and SDH PGL/PCC as familial DNA-repair deficiency syndromes, providing a mechanistic basis to explain their cancer predisposition and suggesting a potentially therapeutic approach for advanced HLRCC and SDH PGL/PCC, both of which are incurable when metastatic.
Cardiac and cancer rehabilitation studies reported employment and income, social support, transport, housing and food security as the most frequent SDH factors influencing attendance, sustained adherence and motivation.
SDH, which is also the complex II of the oxidative respiratory chain, was the first mitochondrial enzyme to be identified having tumour suppressor functions, demonstrating that 80 years after his initial proposal, Otto Warburg may have actually been right when he hypothesized that low mitochondrial respiration was the origin of cancer.
KIT, PDGFRA, NF1 and SDH mutations are alternate initiating events, fostering hyperplasia in gastrointestinal stromal tumours (GISTs), and additional genetic alterations are required for progression to malignancy.
Validation studies revealed dramatically increased sorbitol dehydrogenase concentrations and activity in adenomas and cancer cell lines, along with important changes in the expression of other enzymes in the same (AKR1B1) and related (KHK) pathways.
Germline mutations in SDH genes are responsible for 6% and 9% of sporadic paragangliomas and phaeochromocytomas, respectively, 29% of paediatric cases, 38% of malignant tumours and more than 80% of familial aggregations of paraganglioma and phaeochromocytoma.