Clinical and molecular progress in hereditary paraganglioma

Abstract

Hereditary paraganglioma (PGL) is characterised by genetic predisposition to the development of highly vascular tumours of the paraganglionic tissues and caused by germ line inactivating mutations in the SDHB, SDHC and SDHD subunits of mitochondrial succinate dehydrogenase enzyme complex (SDH; mitochondrial complex II). Recent studies have demonstrated that SDH gene mutations in germ line occur in at least 11% of non-familial head and neck paragangliomas, 8% of non-familial pheochromocytomas, 28% of malignant pheochromocytomas and 33% of extra-adrenal pheochromocytomas. An increasing amount of data suggest that PGL mutations lead to constitutive activation of hypoxia signalling pathways. Genetic and structural models suggest that SDH mutations cause an accumulation of succinate and reactive oxygen species (ROS) which might act as downstream signalling molecules that activate hypoxia inducible pathways. However, many fundamental aspects of PGL pathogenesis, including the mechanism of ROS accumulation, the imprinted transmission pattern of SDHD mutations, and the precise role of SDH in regulation of oxygen homeostasis, remain poorly understood.

LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

“…Pheochromocytoma are often associated with familial tumor syndrome including multiple endocrine neoplasia type 2, neurofibromatosis type 1, and von Hippel-Lindau syndrome. [84][85][86][87] While these tumors are highly differentiated and slow growing, approximately 10% of patients develop metastatic disease and 5 year-survival ranges between 34-60%. [88][89][90] Because of its low growth fraction, metastatic pheochromocytoma has remained a challenge to treat with conventional chemotherapeutic modalities.…”

Mitochondrial respiratory chain complexes: apoptosis sensors mutated in cancer?

“…Indeed, germ-line lossof-function mutations of SDHB, SDHD (cytochrome bS (cybS)) and, more rarely, SDHC (cytochrome bL (cybL)) predispose carriers to head and neck paragangliomas (PGLs), extra-adrenal PGLs and pheochromocytomas (PHs). These SDHB/C/D mutations account for 15% of all hereditary cases (Rutter et al, 2010) and, as they implicate loss of heterozygosity by somatic loss of the normal allele, SDHB/C/D are defined as classical tumour-suppressor genes (Baysal, 2008). It is noteworthy that mutations of the same subunits have also been found in 11-16% of patients with apparently sporadic PGL (Amar et al, 2005;Burnichon et al, 2009) but appear to be absent in sporadic PH (Waldmann et al, 2009;Feichtinger et al, 2011).…”

Overexpression of the natural antisense hypoxia-inducible factor-1 transcript is associated with malignant pheochromocytoma/paraganglioma

“…It was observed that 25-30% of the PGLs are caused by germline mutations of one of the susceptibility genes (Gimenez-Roqueplo et al 2008), i.e. the proto-oncogene RET and the tumor suppressor genes von Hippel-Lindau (VHL), neurofibromatosis type 1 (NF1), and succinate dehydrogenase subunits A-D (SDHA/B/C/D) (Baysal 2008). Mutations in the VHL and/or SDH genes result in a phenotype known as pseudohypoxia (GimenezRoqueplo et al 2001, Kaelin 2007, leading to uncontrolled expression of HIF-1-regulated genes, such as vascular endothelial growth factor (VEGF) which in turn facilitates angiogenesis.…”