MUTATION ANALYSIS OF GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR, A LIGAND FOR AN RET CORECEPTOR COMPLEX, IN MULTIPLE ENDOCRINE NEOPLASIA TYPE-2 AND SPORADIC NEUROENDOCRINE TUMORS/
Dj. Marsh et al., MUTATION ANALYSIS OF GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR, A LIGAND FOR AN RET CORECEPTOR COMPLEX, IN MULTIPLE ENDOCRINE NEOPLASIA TYPE-2 AND SPORADIC NEUROENDOCRINE TUMORS/, The Journal of clinical endocrinology and metabolism, 82(9), 1997, pp. 3025-3028
Causative germline missense mutations in the RET proto-oncogene have b
een associated with over 92% of families with the inherited cancer syn
drome multiple endocrine neoplasia type 2 (MEN 2). MEN 2A is character
ized primarily by medullary thyroid carcinoma (MTC) and pheochromocyto
ma, both tumors of neural crest origin. Parathyroid hyperplasia or ade
noma is also seen in MEN 2A, but rarely in MEN 2B, which has additiona
l stigmata, including a marfanoid habitus, mucosal neuromas, and gangl
ioneuromatosis of the gastrointestinal tract. In familial MTC, MTC is
the only lesion present. Somatic RET mutations have also been identifi
ed in a subset of sporadic MTCs, pheochromocytomas, and rarely, small
cell lung cancer, but not in sporadic parathyroid hyperplasias/adenoma
s or other neuroendocrine tumors. Glial cell line-derived neurotrophic
factor (GDNF) and its receptor molecule GDNFR-alpha, have recently be
en identified as members of the RET ligand binding complex. Therefore,
the genes encoding both GDNF and GDNFR-alpha are excellent candidates
for a role in the pathogenesis of those MEN 2 families and sporadic n
euroendocrine tumors without RET mutations. No mutations were found in
the coding region of GDNF in DNA samples from 9 RET mutation negative
MEN 2 individuals (comprising 6 distinct families), 12 sporadic MTCs,
17 sporadic cases of parathyroid adenoma, and 10 small cell lung canc
er cell lines. Therefore, we find no evidence that mutation within the
coding regions of GDNF plays a role in the genesis of MEN 2 and spora
dic neuroendocrine tumors.