Which of the following best describes the mechanism by which loss of the APC tumor suppressor gene leads to colorectal cancer in familial adenomatous polyposis?

Question

Accepted Answer

A. Loss of APC → increased Wnt/β-catenin signaling → uncontrolled intestinal epithelial proliferation and polyp formation. ## APC Gene and Wnt/β-Catenin Pathway

**Key Point:** APC (adenomatous polyposis coli) is a negative regulator of the Wnt/β-catenin signaling pathway. Loss of APC function leads to constitutive activation of this pathway, driving intestinal epithelial proliferation and polyp formation.

**High-Yield:** APC mutations are the initiating event in ~80% of colorectal cancers and cause familial adenomatous polyposis (FAP) when inherited in germline form.

### Normal APC Function

```mermaid
flowchart TD
  A[Wnt signal OFF] --> B[APC-Axin-GSK3β complex forms]
  B --> C[β-catenin phosphorylated]
  C --> D[β-catenin degraded by proteasome]
  D --> E[TCF/LEF transcription factors inactive]
  E --> F[Intestinal epithelial proliferation SUPPRESSED]
```

### APC Loss in FAP

```mermaid
flowchart TD
  A[APC MUTATED/LOST] --> B[Destruction complex cannot form]
  B --> C[β-catenin accumulates in cytoplasm]
  C --> D[β-catenin enters nucleus]
  D --> E[β-catenin binds TCF/LEF]
  E --> F[Activation of Wnt target genes]
  F --> G[Uncontrolled intestinal epithelial proliferation]
  G --> H[Polyp formation → adenoma → carcinoma]
```

### APC Protein Domains and Function

| Domain | Function |
| --- | --- |
| β-catenin binding region | Binds and sequesters β-catenin |
| Axin binding region | Recruits Axin to destruction complex |
| GSK3β interaction site | Facilitates β-catenin phosphorylation |
| Loss of APC | All regulatory functions lost → constitutive Wnt signaling |

**Clinical Pearl:** Patients with FAP develop hundreds to thousands of adenomatous polyps throughout the colon by age 20–30 years. Without prophylactic colectomy, colorectal cancer is virtually inevitable by age 40–50 years. The polyps arise from loss of APC in intestinal stem cells, allowing uncontrolled Wnt-driven proliferation.

**Mnemonic:** **APC = Adenomatous Polyposis Coli** — the "brake" on Wnt signaling. When APC is lost, the Wnt "accelerator" runs unchecked.

**Warning:** ~~Do not confuse APC mutations with mismatch repair gene mutations~~ — APC mutations cause FAP with adenomatous polyps, while MLH1/MSH2 mutations cause Lynch syndrome with fewer polyps but high cancer risk.

Answer

B. Loss of APC → impaired mismatch repair → microsatellite instability → colorectal cancer

Answer

C. Loss of APC → defective apoptosis → accumulation of damaged cells → colorectal cancer

Answer

D. Loss of APC → loss of cell cycle checkpoint control → uncontrolled G1/S progression → colorectal cancer

Which of the following best describes the mechanism by which loss of the APC tumor suppressor gene leads to colorectal cancer in familial adenomatous polyposis?

Explanation

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