A 40-year-old woman has a medullary thyroid carcinoma. Her serum calcitonin is markedly elevated and she is found to have a germline RET proto-oncogene mutation. This mutation is BEST classified as which type of gain-of-function alteration?

• A Chromosomal translocation creating a fusion oncogene
• B Gene amplification
• C Promoter hypomethylation
• D Point mutation causing constitutive receptor tyrosine kinase activation ✓

Explanation

Germline point mutations in RET (especially codon 634 in MEN2A and codon 918 in MEN2B) cause constitutive activation of the RET receptor tyrosine kinase without ligand binding, driving malignant transformation of parafollicular C-cells. This is a classic gain-of-function proto-oncogene mutation; chromosomal rearrangements (RET/PTC) occur in papillary, not medullary, thyroid carcinoma.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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