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 **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 ```