Molecular biology of pheochromocytomas and paragangliomas

Pheochromocytomas and paragangliomas are catecholamine-secreting neural crest-derived tumors that arise from the adrenal medulla or extraadrenal sympathetic paraganglia, respectively. These tumors are genetically heterogeneous and an increasing fraction can be caused by germline mutations in at least six distinct genes, a finding that has challenged old paradigms of pheochromocytoma biology. In this chapter, we discuss the various hereditary mutations that cause pheochromocytoma and paraganglioma, and describe recent molecular and genomic advances that are uncovering pathogenic signals responsible for tumorigenesis. Similarities amongst the various genetic forms of these tumors are being revealed which can be traced back to the developing neural crest. Despite signaling overlaps, well-established as well as emerging genotype-phenotype correlations of the different hereditary forms imply unique features of each gene that carries translational relevance. Current evidence suggests the existence of additional susceptibility genes that might account for genetically undefined pheochromocytomas and paragangliomas. The progress of recent years in understanding disease pathogenesis is expected to improve patient screening and, in the long term, be translated into broader therapeutic options.