Mouse Models of Human Familial Paraganglioma

Tumor suppressor genes (TSGs) protect normal cells from tumorigenesis (Lasko et al., 1991; Sherr, 2004). Except in cases of haploinsufficiency, heterozygosity for a non-functional TSG allele protects a cell from tumor formation because the functional TSG allele produces a functional protein. Loss of heterozygosity (LOH) is a mechanism by which the remaining wild type tumor suppressor allele is lost, resulting in tumor formation (Lasko et al., 1991; Sherr, 2004). Loss of TSG expression may also occur by epigenetic silencing. The probability of a "second hit" follows a Poisson distribution with the number of tumors and time of incidence being variable in heterozygous carriers (Shao et al., 1999). Many TSGs have been identified. Such genes play roles in many cellular functions including cell cycle checkpoint control, mitogenic signaling pathways, protein turnover, DNA damage, hypoxia and other stress responses (Sherr, 2004). Surprisingly, the SdhB, SdhC, and SdhD subunits of the metabolic enzyme succinate dehydrogenase (SDH), have also been identified as TSGs for neuroendocrine tumors such as paraganglioma (PGL) and pheocheomocytoma (PHEO). PGLs are rare (1:300,000) tumors of neuroectodermal origin derived from paraganglia, a diffuse neuroendocrine system dispersed from the base of the skull to the pelvic floor (Baysal, 2002). PGLs are highly vascularized tumors that can originate in either the sympathetic or parasympathetic nervous systems (Baysal, 2002; Pacak et al., 2001). Patients with PGL tumors that secrete catecholamines present symptoms of catecholamine excess including palpitations. The predominant clinical features of nonchromaffin PGLs are cranial nerve palsies and tinnitus; however, a small proportion of these nonchromaffin PGLs secrete catecholamines (Dluhy, 2002). A hereditary PGL predisposition is involved in at least 30% of cases (Maher & Eng, 2002; Bryant et al., 2003). Individuals with familial predisposition display at least 40% penetrance and a more severe presentation than those with the sporadic form of the disease. Extra-adrenal pheochromocytomas are estimated to be malignant in 40% of cases (Young et al., 2002). There is currently no effective cure for malignant PGL.