A 28-year-old man with a family history of colorectal cancer undergoes genetic testing and colonoscopy. He is found to have hundreds of adenomatous polyps throughout the colon. Genetic testing confirms a germline mutation in the APC tumor suppressor gene on chromosome 5q21, consistent with the condition marked **A** in the diagram. Which of the following best explains the molecular mechanism by which loss of APC function leads to polyp formation in this syndrome?

Question

Accepted Answer

D. Loss of APC prevents beta-catenin degradation via the destruction complex, leading to nuclear accumulation of beta-catenin and TCF/LEF-driven transcription of MYC and cyclin D1. ## Why option 1 is correct

The APC protein is a critical component of the destruction complex (along with GSK-3β and axin) that normally promotes beta-catenin degradation. Loss of APC function in familial adenomatous polyposis (marked **A**) prevents this degradation, causing beta-catenin to accumulate in the cytoplasm, translocate to the nucleus, and activate TCF/LEF transcription factors. This drives expression of oncogenes MYC and cyclin D1, initiating the adenoma-carcinoma sequence and explaining the hallmark hundreds to thousands of colonic adenomatous polyps by the second decade. This is the gatekeeper mutation in FAP pathogenesis (Sabiston 21e; ACG Guideline Hereditary GI Cancer Syndromes 2015).

## Why each distractor is wrong

- **Option 2**: Loss of APC does not increase p53; rather, p53 mutations occur later in the adenoma-carcinoma sequence. p53 is a tumor suppressor that normally inhibits proliferation, not drives it.
- **Option 3**: Impaired mismatch repair and microsatellite instability are hallmarks of Lynch syndrome (marked **C**), not familial adenomatous polyposis. FAP is caused by APC mutations, not mismatch repair defects.
- **Option 4**: SMAD signaling and TGF-beta are involved in other polyposis syndromes (e.g., juvenile polyposis, marked **D**), not the Wnt/beta-catenin pathway disruption that defines FAP.

**High-Yield:** APC loss → beta-catenin accumulation → Wnt pathway activation → MYC/cyclin D1 upregulation = the gatekeeper mutation initiating FAP adenoma-carcinoma sequence.

[cite: Sabiston 21e; ACG Guideline Hereditary GI Cancer Syndromes 2015]

Answer

A. Loss of APC impairs mismatch repair proteins, resulting in microsatellite instability and adenoma development

Answer

B. Loss of APC increases p53 expression, which drives uncontrolled cell proliferation and polyp formation

Answer

C. Loss of APC activates SMAD signaling, causing excessive TGF-beta-mediated epithelial cell growth

Explanation

Why option 1 is correct

Why each distractor is wrong

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