Expression analysis of RET and the GDNF/GFRalpha-1 and NTN/GFRalpha-2 ligand complexes in pheochromocytomas and paragangliomas.

Abstract

Pheochromocytoma and its extra-adrenal counterpart paraganglioma are rare catecholamine producing tumors which usually occur sporadically but may also be a part of neuroendocrine tumor syndromes such as multiple endocrine neoplasia type 2A (MEN 2A). Activating mutations of the RET proto-oncogene which is the underlying cause of MEN 2A, is also seen in approximately 10% of sporadic pheochromocytomas. Glial cell line derived neurotrophic factor (GDNF) and neurturin (NTN) have been shown to function as independent ligands to RET, binding in a complex with the membrane-bound receptors GFRalpha-1 and GFRalpha-2 respectively. Here we have investigated the mRNA expression of RET and its ligand complexes, GDNF/GFRalpha-1 and NTN/GFRalpha-2, in a panel of pheochromocytomas and paragangliomas using mRNA in situ hybridization. RET expression was evident in normal adrenal medulla, and in 13/15 pheochromocytomas, including 5/5 MEN 2A associated tumors, but only in 1/10 paragangliomas. The frequent expression of RET in the pheochromocytomas suggest that this gene might be involved in the tumorigenesis. However, no expression of GDNF/GFRalpha-1 or NTN/GFRalpha-2 could be detected in any of the 25 tumors analyzed, suggesting that these ligand complexes are not important in the development of pheochromocytoma or paraganglioma.