Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)
Hereditary paraganglioma and pheochromocytoma syndromes were a group of syndromes closely associated with the development of chromaffin cell tumors, namely, pheochromocytomas and, their extra-adrenal counterparts, paragangliomas (Fig. 8.5). It was initially postulated that only 10% of such tumors possessed a genetic component, but recent gene studies have confirmed that as high as 35% of these neoplasms without a definable syndrome are caused by a hereditary predisposition . Since 2000, it became recognized that many of these syndromes were related to an alteration in a common enzyme succinate dehydrogenase; hence, the syndromes are considered to have succinate dehydrogenase deficiency (SDH). There are multiple constituents to the SDH enzyme complex that function together as an important enzyme in the Krebs cycle, converting succinate to fumarate. Located in the inner mitochondrial membrane adjacent to the matrix, SDH not only participates in the Krebs cycle but also as complex II in the electron transport chain. Its dysregulation directly results in hypoxic metabolism and aggressive neoplastic growth consistent with the Warburg effect .
Pertaining to hereditary kidney cancers, however, alterations in only SDH subunits B/C/D have been implicated. This association was first characterized in 2004, and it was later found that 5% of familial RCC without a diagnosed syndrome could be mapped to SDHB germline mutation [51, 52]. A germline mutation in genes coding for the other subunits SDHC and SDHD has also been linked to an increased risk of RCC. Similar to HLRCC, kidney tumors in the setting of SDH tend to follow an aggressive course. In addition to chromaffin and kidney tumors, recent findings suggest that SDH mutations may also increase the risk of gastrointestinal stromal tumors .
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