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Mutation Analysis of Glial Cell Line-derived Neurotrophic Factor (GDNF), a Ligand for the RET/GDNF Receptor Complex, in Sporadic Phaeochromocytomas¹

Translational Research Laboratory, Division of Cancer Epidemiology and Control, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115 [P. L. M. D., C. E.]; Department of Endocrinology, St. Bartholomew's Hospital, London EC1A 7BE, United Kingdom [P. L. M. D., A. B. G.]; Endocrine Genetics Unit. University of Sao Paulo Medical School, Sao Paulo 02146-913, Brazil [S. P. A. T.]; Departments of Paediatrics and Pathology, Queen's University, Kingston, Ontario, K7L 3N6 Canada [L. M. M.]; and Human Molecular Genetics Group [E. R. M.] and Cancer Research Campaign Human Cancer Genetics Research Group [C. E.], University of Cambridge, Cambridge CB2 2QQ, United Kingdom

Phaeochromocytomas usually occur sporadically but may also be a feature of three autosomal dominantly inherited cancer syndromes, multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and, very rarely, type 1 neurofibromatosis. Germ-line missense mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, cause multiple endocrine neoplasia type 2. In VHL, germ-line mutations in one of the three exons of the VHL tumor suppressor gene have been found in the majority of families. Whereas somatic mutations in the VHL gene have been common in sporadic renal cell carcinoma, a component cancer of VHL, somatic mutations in the RET and VHL genes together have been found in approximately 10% of sporadic phaeochromocytomas. Hence, other genes must also contribute to the pathogenesis of sporadic phaeochromocytomas. Recent data have suggested that glial cell line-derived neurotrophic factor (GDNF) is a ligand for RET and acts via a heterotetrameric receptor complex that includes GDNF receptor , which provides ligand binding capabilities, and RET, which provides the signaling component. Thus, both GDNF and GDNFR- are plausible candidate genes for involvement in the pathogenesis of phaeochromocytomas. To investigate the role of GDNF in sporadic phaeochromocytomas, we scanned a panel of 22 tumors. Among these samples, only a conservative sequence variant was detected in exon 2 of GDNF. No disease-associated somatic GDNF mutations or gross gene amplification were detected in these tumors, suggesting only a minor role for GDNF in the genesis of phaeochromocytomas.

¹ Supported by the Fundaclo de Amparo a Pesquisa do Estado de Sao Paulo, Brazil (FAPESP 94/2025-8), the Lawrence and Susan Marx Investigatorship in Human Cancer Genetics, the Markey Charitable Trust, the Charles A. Dana Foundation, and a Patterson Fellowship.

² To whom requests for reprints should be addressed, at Dana-Farber Cancer Institute D920C, 44 Binney Street, Boston, MA 02115-6084. Phone: (617) 632-5632; Fax: (617) 632-4280; E-mail: charis_eng@macmailgw.dfci.harvard.edu.

Received 8/19/96. Accepted 11/ 8/96.

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