A 17-year-old woman with a family history of familial adenomatous polyposis (FAP) undergoes colonoscopy. The structure marked **A** in the diagram shows a dense carpet of hundreds to thousands of small adenomatous polyps throughout the colon with virtually no normal-appearing intervening mucosa. Genetic testing confirms a heterozygous APC truncating mutation at codon 1309. Which of the following best explains the molecular mechanism underlying the profuse polyposis phenotype seen in this patient?

Question

Accepted Answer

C. Loss of APC function leads to nuclear accumulation of beta-catenin, increased transcription of c-Myc and cyclin D1, and uncontrolled colonic epithelial proliferation. ## Why option 1 is right

The structure marked **A** — the carpet of hundreds to thousands of adenomatous polyps — is the direct consequence of loss-of-function mutations in the APC tumor suppressor gene. APC normally regulates the WNT/beta-catenin signaling pathway by promoting degradation of beta-catenin. When APC is lost (as in this patient's germline truncating mutation at codon 1309), beta-catenin accumulates in the nucleus, leading to uncontrolled transcription of oncogenes including c-Myc and cyclin D1. This drives uncontrolled colonic epithelial proliferation and adenoma formation. This mechanism is the foundational molecular basis of FAP and is explicitly stated in Sleisenger and Fordtran 11e Ch 126 and NCCN FAP guidelines.

## Why each distractor is wrong

- **Option 2**: APC mutations are loss-of-function, not gain-of-function. Increased apoptosis would reduce, not increase, polyp burden. This contradicts the pathophysiology of FAP.
- **Option 3**: While p53 mutations are important in the adenoma-to-carcinoma sequence in FAP, they are not the primary driver of the profuse adenoma phenotype. The germline defect in FAP is in APC, not p53. p53 mutations are acquired later during malignant transformation.
- **Option 4**: COX-2 overexpression may contribute to polyp growth and is the target of chemoprevention with NSAIDs and celecoxib, but it is not the primary molecular mechanism of the profuse polyposis phenotype. COX-2 dysregulation is secondary to APC loss.

**High-Yield:** APC loss → beta-catenin accumulation → c-Myc/cyclin D1 upregulation → uncontrolled epithelial proliferation = FAP adenoma carpet.

[cite: Sleisenger and Fordtran 11e Ch 126; NCCN Genetic Familial High-Risk Assessment 2024; Vasen Gut 2008 FAP guidelines]

Answer

A. Gain-of-function mutation in APC enhances WNT/beta-catenin signaling and increases epithelial cell apoptosis

Answer

B. Overexpression of COX-2 in colonic epithelium drives prostaglandin-mediated polyp growth independent of APC signaling

Answer

D. Inactivation of the tumor suppressor p53 on chromosome 17 prevents cell cycle arrest and allows adenoma formation

Explanation

Why option 1 is right

Why each distractor is wrong

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