A 45-year-old patient with a medullary thyroid carcinoma is found to have a RET proto-oncogene mutation. Which mechanism best describes how the mutant RET protein drives neoplastic transformation?

• A Loss of RET protein function leading to failure of apoptosis
• B RET acting as a tumor suppressor gene requiring biallelic inactivation
• C RET mutation causing overexpression of E-cadherin
• D Constitutive activation of RET tyrosine kinase signaling independent of ligand binding ✓

Explanation

RET is a receptor tyrosine kinase proto-oncogene. In MEN2/familial medullary thyroid carcinoma, gain-of-function point mutations cause constitutive (ligand-independent) tyrosine kinase activation, triggering uncontrolled downstream signaling via RAS-ERK and PI3K-AKT pathways. Unlike tumor suppressors requiring biallelic loss, a single RET gain-of-function mutation is oncogenic. This is the classic example of an activating mutation in a receptor tyrosine kinase.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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