A patient's tumor shows strong nuclear accumulation of beta-catenin on immunohistochemistry. This pattern is the molecular footprint of mutation in which pathway component?

• A Gain-of-function APC mutation driving nuclear beta-catenin translocation
• B Loss of function of Axin2 causing nuclear retention of unphosphorylated beta-catenin
• C Activating mutation in E-cadherin releasing cytoplasmic beta-catenin
• D Phosphorylation-site mutation in CTNNB1 preventing GSK-3beta-mediated degradation ✓

Explanation

Nuclear beta-catenin accumulation most commonly results from activating mutations in CTNNB1 at the phosphorylation sites (Ser/Thr residues in exon 3) that are normally targeted by the destruction complex (GSK-3beta/APC/Axin). This prevents ubiquitin-mediated proteasomal degradation, so beta-catenin translocates to the nucleus to drive TCF/LEF target gene transcription. Loss-of-function APC mutations also activate Wnt signalling but through a different mechanism (disrupting the destruction complex scaffold), and wild-type APC inhibits rather than drives beta-catenin signalling. Axin2 loss is a secondary regulatory mutation; E-cadherin mutations do not activate nuclear signalling.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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