title: Molecular analysis of the RET proto-oncogene in patients with sporadic medullary thyroid carcinoma: a novel point mutation in the extracellular cysteine-rich domain.
abstract: Germline point mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia type 2 (2A and 2B) and familial medullary thyroid carcinoma. On the other hand, somatic point mutations of RET have been described in a subset of sporadic medullary thyroid carcinomas (MTCs). We examined tumor and blood DNA of thirteen apparently sporadic MTC patients for mutations in RET exons 10, 11, 13, 15 and 16 to determine whether they had true sporadic tumors or either de novo or occult germline mutations. Three different somatic missense mutations were documented in seven patients. In five patients a mutation in exon 16, codon 918, (ATG-->ACG) causing a Met-->Thr substitution was found. In the remaining two patients the mutation affected exon 11: codon 630 in one case and codon 634 in the other. In both cases a T-->C transversion was identified causing a Cys-->Arg substitution. In conclusion, absence of a germline mutation in RET exons 10, 11, 13 or 16 is evidence against an inherited form in all cases. In seven patients, identification of a somatic mutation supported the previous clinical diagnosis of sporadic medullary thyroid carcinoma; in one of them we identified a hitherto undescribed somatic point mutation at codon 630.
authors.affiliation: Laboratório de Biologia Molecular, Instituto Português de Oncologia, Lisboa, Portugal.
authors.forename: M J
authors.initials: MJ
authors.lastname: Bugalho
authors.forename: J P
authors.initials: JP
authors.lastname: Frade
authors.forename: J R
authors.initials: JR
authors.lastname: Santos
authors.forename: E
authors.initials: E
authors.lastname: Limbert
authors.forename: L
authors.initials: L
authors.lastname: Sobrinho
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D002116:Calcitonin / Q000032:analysis; D018276:Carcinoma, Medullary / Q000737:chemistry* / Q000145:classification / Q000235:genetics; D003545:Cysteine / Q000032:analysis*; D004273:DNA, Neoplasm / Q000032:analysis / Q000097:blood; D029721:Drosophila Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D005091:Exons; D005109:Extracellular Matrix / Q000737:chemistry*; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009377:Multiple Endocrine Neoplasia / Q000737:chemistry* / Q000145:classification / Q000235:genetics; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000032:analysis* / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D011519:Proto-Oncogenes; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis* / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000737:chemistry* / Q000145:classification / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D002116:Calcitonin; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; D003545:Cysteine