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Energy and metabolic alterations in predisposition to pheochromocytomas and paragangliomas: the so-called Warburg (and more) effect, 15 years on.

It happened in Pittsburgh, Pennsylvania, USA, in the year 2000. Bora Baysal, MD, PhD, a Turkish molecular biologist and trained pathologist, collaborated with physicians from Leiden, The Netherlands, who took care of the famous and etiologically puzzling Dutch paraganglioma family. He and his collaborators mapped the susceptibility gene locus to 11q23 and linked it to a gene encoding one of the four subunits of succinate dehydrogenase (mitochondrial complex II, SDHD), an enzyme that lies at the all-important crossroads of energy production, the Krebs tricarboxylic acid cycle and the glycolytic chain. The bombshell was dropped in the journal Science 15 years ago (Baysal et al. 2000). Paraganglioma syndrome ‘type 1’ (PGL1) finally had a genetic etiology: germline mutations of the SDHD gene. Within months, the SDH components B and C (together with SDHD umbrellaed under SDHx) were shown to predispose to similar tumors, if the respective genes (SDHB and SDHC) were mutated (Niemann & Müller 2000, Astuti et al. 2001). Soon there was evidence that not only head and neck paragangliomas but also pheochromocytomas and paragangliomas of the retroperitoneum and chest were caused by germline mutations of these genes (Gimm et al. 2000, Eng et al. 2003). These paradigm-shifting discoveries led to an onslaught, which continues today, of multiple studies both in paraganglioma and pheochromocytoma but more broadly into energy production and metabolism in carcinogenesis. Lest we be caught up in this marathon sprint, let us pause to loudly celebrate the 15th anniversary of this discovery. Let us linger for a moment to enjoy and acknowledge all the achievements and progress in this field, highlighted by this special issue of Endocrine-Related Cancer. Baysal & Maher (2015), aptly, kick off this special issue with an overview of the genetics of the first two genes, SDHB and SDHD, in paraganglioma and pheochromocytoma. SDHD became the first enzyme demonstrating that damage of the mitochondria is really a key feature in tumor cells opening a new chapter on the Warburg effect, the aerobic glycolysis by tumor cells. The paraganglionic tumors are, meanwhile, closely linked to mitochondrial insufficiency after the identification of structural abnormalities in three key enzymes, SDH, fumarate hydratase (FH) and malate dehydrogenase (MDH). Mannelli et al. (2015) present an erudite review on metabolism and pheochromocytoma/paraganglioma. As appears typical of translational genetics, rapid scientific progress precedes clinical practice. For the latter, the neoplasia risk spectra had to be defined regarding age of manifestation, tumor location, tumor number, malignant tumors and tumor growth as well as longer-term outcome (Neumann et al. 2002, 2004, Gimenez-Roqueplo et al. 2003, Schiavi et al. 2005, Benn et al. 2006). In parallel, judicious effective clinical management had to be adjudicated, including adequate treatment for symptomatic and also for pre-symptomatically detected tumors. Organ sparing and endoscopic operation techniques were developed. With in-depth investigation and longitudinal follow-up, genetic counselors became equipped with risk estimates, incomplete penetrance (e.g., SDHB) and maternal imprinting (e.g., SDHD). With the diverse