- Identify the molecular genetic aberrations contributing to the development of pheochromocytomas
- Identify the molecular genetic aberrations contributing to the development of other adrenal tumors, such as those causing hyperaldosteronism and hypercortisolism
Pheochromocytomas are rare catecholamine-producing tumors that derive from adrenomedullary tissue in about 80% of cases and from extra-adrenal chromaffin tissue in about 20% of cases. Pheochromocytomas arising in extra-adrenal tissue are commonly called paragangliomas. Regardless of location, pheochromocytomas share similar histopathological characteristics. Pheochromocytomas can cause hypertension via high circulating catecholamine levels, accounting for approximately 0.05% to 0.1% of cases of sustained hypertension. About 50% of patients with pheochromocytoma has only episodic or no hypertension. It has been estimated that in the United States approximately 40,000 persons have pheochromocytoma, with newly diagnosed pheochromocytoma averaging 800 to 1600 cases per year in the general population.
Sporadic vs. Familial Pheochromocytoma
Pheochromocytoma occurs either sporadically or in four known familial syndromes—multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau (VHL) disease, neurofibromatosis type 1 (NF 1), and succinate dehydrogenase (SDH) gene mutation. Familial pheochromocytoma may appear to occur outside any of these four syndromes. The molecular genetic abnormalities underlying sporadic pheochromocytoma are largely unknown.
Patients with MEN2 have hyperplasia or tumors of the adrenal, thyroid, and parathyroid glands that are often multicentric within the glands. Both MEN2A and MEN2B feature pheochromocytoma. MEN2 is inherited as an autosomal dominant trait with incomplete penetrance and variable expression. Pheochromocytoma occurs in 30% to 50% of patients with MEN2. VHL disease is also inherited as an autosomal dominant trait, in which 15-20% patients develop pheochromocytoma. More than 300 vhl germline mutations have been identified so far, 32 of them associated with pheochromocytoma. The vhl tumor suppressor gene is located on chromosome 3p25-26. Recently, pheochromocytoma susceptibility has been associated with germline mutations of the succinate dehydrogenase gene family. In recent studies it has been found that about 4-12% of sporadic pheochromocytomas and in up to 50% of familial pheochromocytomas have either SDHD or SDHB mutation and there is a strong association of SDHD and SDHB mutations with the presence of extra-adrenal multifocal pheochromocytomas. NF 1, also inherited as an autosomal dominant trait with variable expression, is the most common familial cancer syndrome predisposing to pheochromocytoma, affecting about 1:4,000 individuals in the general population. The risk of pheochromocytoma in NF 1, however, is small—about 1%. The nf1 gene is a large tumor suppressor gene located on chromosome 17q11.2. Familial pheochromocytoma occurring without any clear link to VHL disease, NF 1, or MEN2 is usually inherited as an autosomal dominant trait. Pheochromocytoma may also occur as a part of Carney’s triad, a sporadic disease that includes gastric leiomyosarcoma, pulmonary chondroma, and extra-adrenal pheochromocytoma. Only 79 cases have been reported to date20. Paraganglioma, arising in extra-adrenal chromaffin tissue, may be sporadic or familial. Paragangliomas account for 20% of pheochromocytomas in adults and 30-50% in children.
It is not yet possible to predict when and how severe a pheochromocytoma will be manifest in these diseases, since the molecular mechanisms by which the genotypic changes predispose to development of pheochromocytoma remain unknown. Preliminary results of glucagon stimulation testing, plasma metanephrines and other tests suggest phenotypic differences among tumors, as discussed below.
Recently, we have shown that the Rb-interacting zinc finger gene (RIZ1), located at chromosome 1p36, is a bona fide tumor suppressor gene since mutational alterations and loss of function have been detected in human tumors. We recently showed that the RIZ1 gene is expressed in the adrenal medulla and may be implicated in the tumor development of pheochromocytomas. Other, yet to be identified genetic abnormalities at chromosome 1q may also be implicated in the disease.
The molecular biology of other lesions of the adrenal is largely unknown.
Despite recent advances in the understanding of the pathophysiology and molecular genetics of adrenal tumors, a number of important scientific questions remain.