Which of the following tumor suppressor genes is most commonly inactivated in familial adenomatous polyposis (FAP)?

Question

Accepted Answer

B. APC. ## APC Gene Inactivation in Familial Adenomatous Polyposis ### APC — The Gatekeeper of Colorectal Cancer **Key Point:** Germline APC mutations are responsible for 100% of familial adenomatous polyposis cases. APC is also inactivated in ~80% of sporadic colorectal cancers. **High-Yield:** APC inactivation is the initiating event in the adenoma-carcinoma sequence: 1. APC loss → Wnt pathway activation → adenoma formation 2. KRAS mutation → adenoma growth 3. TP53 loss → malignant transformation ### APC Function and Mechanism **Mnemonic:** **"APC = Adenomatous Polyposis Coli"** — the protein that regulates Wnt/β-catenin signaling. **Clinical Pearl:** Patients with FAP develop hundreds to thousands of colorectal adenomas by age 40 and have nearly 100% lifetime risk of colorectal cancer without prophylactic colectomy. ### Comparison of Tumor Suppressors in Colorectal Cancer | Gene | Role in CRC | Frequency in FAP | Frequency in Sporadic CRC | | --- | --- | --- | --- | | **APC** | Initiating event, Wnt pathway | 100% (germline) | 80% | | TP53 | Late event, malignant transformation | ~50% of adenomas | 50–70% | | SMAD4 | TGF-β pathway, late adenoma | <5% germline | 30% of cancers | | PTEN | PI3K/AKT pathway | Rare | <5% | **Warning:** While TP53 is the most commonly inactivated gene across ALL cancers, APC is the defining gene for FAP specifically and is inactivated first in the adenoma-carcinoma sequence. ### Adenoma-Carcinoma Sequence (Fearon-Vogelstein Model) ```mermaid flowchart TD A[Normal epithelium]:::outcome --> B[APC loss]:::action B --> C[Early adenoma]:::outcome C --> D[KRAS activation]:::action D --> E[Intermediate adenoma]:::outcome E --> F[TP53 loss]:::action F --> G[Late adenoma/Carcinoma]:::urgent ```

Answer

A. SMAD4

Answer

C. PTEN

Answer

D. TP53

Which of the following tumor suppressor genes is most commonly inactivated in familial adenomatous polyposis (FAP)?

Explanation

APC Gene Inactivation in Familial Adenomatous Polyposis

APC — The Gatekeeper of Colorectal Cancer

APC Function and Mechanism

Comparison of Tumor Suppressors in Colorectal Cancer

Adenoma-Carcinoma Sequence (Fearon-Vogelstein Model)

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Gene	Role in CRC	Frequency in FAP	Frequency in Sporadic CRC
APC	Initiating event, Wnt pathway	100% (germline)	80%
TP53	Late event, malignant transformation	~50% of adenomas	50–70%
SMAD4	TGF-β pathway, late adenoma	<5% germline	30% of cancers
PTEN	PI3K/AKT pathway	Rare	<5%