Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC.
We have analysed 118 families with inherited medullary thyroid carcinoma (MTC) for mutations of the RET proto-oncogene. These included cases of multiple endocrine neoplasia types 2A (MEN 2A) and 2B (MEN 2B) and familial MTC (FMTC). Mutations at one of 5 cysteines in the extracellular domain were found in 97% of patients with MEN 2A and 86% with FMTC but not in MEN 2B patients or normal controls. 84% of the MEN2A mutations affected codon 634. MEN 2A patients with a Cys634 to Arg substitution had a greater risk of developing parathyroid disease than those with other codon 634 mutations. Our data show a strong correlation between disease phenotype and the nature and position of the RET mutation, suggesting that a simple, constitutive activation of the RET tyrosine kinase is unlikely to explain the events leading to MEN 2A and FMTC.
Mulligan
L M
LM
Department of Pathology, University of Cambridge, UK.
Eng
C
C
Healey
C S
CS
Clayton
D
D
Kwok
J B
JB
Gardner
E
E
Ponder
M A
MA
Frilling
A
A
Jackson
C E
CE
Lehnert
H
H
D001483:Base Sequence; D018276:Carcinoma, Medullary / Q000235:genetics*; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D029721:Drosophila Proteins; D005091:Exons; D006801:Humans; D008969:Molecular Sequence Data; D009377:Multiple Endocrine Neoplasia / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D011519:Proto-Oncogenes; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics*
D017931:DNA Primers; D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila