A 45-year-old man with MEN2A syndrome has prophylactic thyroidectomy. Histology shows C-cell hyperplasia progressing to medullary thyroid carcinoma (MTC). The RET proto-oncogene mutation responsible for MEN2A most commonly involves which codon, and which receptor signalling pathway is constitutively activated?
- A Codon 918 (methionine-to-threonine substitution) — substrate pocket change causing autophosphorylation in MEN2B
- B Codon 634 mutation activates VEGFR2 co-receptor signalling driving angiogenesis
- C Codon 634 (cysteine substitution) — constitutive receptor dimerisation and tyrosine kinase activation via RET receptor tyrosine kinase ✓
- D Codon 768 mutation causes nuclear localisation of RET with activation of p53 pathway
Explanation
MEN2A is caused by germline gain-of-function mutations in the RET proto-oncogene, most commonly at codon 634 (exon 11) — specifically cysteine-634 substitution (most often C634R, C634Y). Cysteine residues in the extracellular cysteine-rich domain of RET normally form intramolecular disulphide bonds; substitution of Cys634 forces unpaired cysteine residues to form intermolecular disulphide bonds between two RET monomers, causing constitutive ligand-independent dimerisation and continuous tyrosine kinase activation. This drives constitutive downstream signalling via RAS-ERK, PI3K-AKT, and STAT3 pathways. MEN2B is caused by M918T mutation (different codon), which changes substrate specificity. Codon 634 mutations in MEN2A carry high penetrance for MTC and phaeochromocytoma. Prophylactic thyroidectomy timing is guided by mutation codon risk stratification (ATA Risk A-D).
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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Written and medically reviewed by the StethoPrep medical team.