RET proto-oncogene point mutations in sporadic neuroendocrine tumors.
We investigated the possible role of the RET proto-oncogene, which has recently been identified as the susceptibility gene for multiple endocrine neoplasia type 2, in the development of sporadic neuroendocrine tumors from different locations. DNA extracted from paraffin-embedded specimens of 112 neuroendocrine tumors was screened for somatic RET point mutations in exons 10, 11, 13, 15, and 16, where recently oncogenic mutations have been described in a subset of sporadic medullary thyroid carcinomas and pheochromocytomas. Methods employed included nonisotopic PCR-based single strand conformation polymorphism (PCR-SSCP) analysis, heteroduplex gel electrophoresis, and restriction enzyme digestion. The nucleotide sequence of samples with aberrant band patterns was identified by nonisotopic direct sequencing of PCR-amplified DNA. Forty-four percent (7/16) of sporadic medullary thyroid carcinomas and 15% (3/20) of pheochromocytomas contained a somatic, heterozygous point mutation at codon 918 of exon 16 (ATG --> ACG) causing a Met --> Thr substitution. None of the remaining 4 parathyroid adenomas, 8 pituitary adenomas, 17 pancreatic neuroendocrine tumors, 11 pulmonary and 10 gastrointestinal carcinoids, 7 small cell lung carcinomas, 5 neuroblastomas, 10 malignant melanomas, or 4 schwannomas contained mutations in any of the five RET exons tested. Although the numbers of each investigated neuroendocrine tumor type are small, our data indicate that oncogenic RET proto-oncogene mutations are involved in the formation of a subset of sporadically occurring medullary thyroid carcinomas and pheochromocytomas but do not appear to be generally important in the formation of other types of sporadically occurring neuroendocrine tumors.
Komminoth
P
P
Division of Cell and Molecular Pathology, University of Zürich, Switzerland. paulkom@pathol.unizh.ch
Roth
J
J
Muletta-Feurer
S
S
Saremaslani
P
P
Seelentag
W K
WK
Heitz
P U
PU
D000310:Adrenal Gland Neoplasms / Q000235:genetics; D001483:Base Sequence; D018276:Carcinoma, Medullary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D029721:Drosophila Proteins; D005091:Exons; D006801:Humans; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D018358:Neuroendocrine Tumors / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics
D004273:DNA, Neoplasm; D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D015335:Molecular Probes; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila