A 35-year-old Indian man with a known history of familial adenomatous polyposis (FAP) presents with right lower abdominal pain and bloody diarrhea. Colonoscopy reveals hundreds of adenomatous polyps throughout the colon and a 4 cm mass in the sigmoid colon with features suspicious for malignancy. Histopathology confirms adenocarcinoma. Genetic analysis confirms a frameshift mutation in the APC gene. Which of the following best explains the high cancer risk in this patient?

Explanation

## Clinical Context Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by germline mutations in the APC (adenomatous polyposis coli) tumor suppressor gene. Patients develop hundreds to thousands of adenomatous polyps in the colon, with near-100% risk of colorectal cancer by age 50 if untreated. ## APC Gene Function and the Wnt Pathway **Key Point:** APC is a critical negative regulator of the Wnt/β-catenin signaling pathway. Loss of APC function leads to constitutive activation of this pathway, driving uncontrolled cell proliferation and polyp formation. ## Normal APC Function 1. **In the absence of Wnt signal:** APC forms a destruction complex with Axin and GSK-3β that phosphorylates β-catenin, targeting it for proteasomal degradation. β-catenin levels remain low. 2. **β-catenin accumulation is prevented:** Low β-catenin cannot enter the nucleus, so TCF/LEF transcription factors remain transcriptionally inactive. ## Pathophysiology in APC Mutation ```mermaid flowchart TD A[Normal APC]:::action --> B[β-catenin phosphorylated & degraded]:::outcome B --> C[Low nuclear β-catenin]:::outcome C --> D[TCF/LEF transcription factors inactive]:::outcome D --> E[Normal Wnt target genes OFF]:::outcome F[APC Mutation/Loss]:::urgent --> G[Destruction complex disrupted]:::outcome G --> H[β-catenin accumulates]:::urgent H --> I[High nuclear β-catenin]:::urgent I --> J[TCF/LEF transcription factors ACTIVE]:::urgent J --> K[Oncogenic Wnt target genes ON]:::urgent K --> L[Cell proliferation, polyp formation, cancer risk]:::urgent ``` ## Downstream Consequences of Wnt/β-Catenin Activation **High-Yield:** Constitutive Wnt/β-catenin signaling in APC-mutant cells activates transcription of: - **c-MYC** — drives proliferation - **Cyclin D1** — promotes G1/S transition - **Survivin** — inhibits apoptosis - **Other oncogenic transcription factors** — sustain the transformed phenotype **Clinical Pearl:** The adenoma-carcinoma sequence in FAP: 1. **Initiation:** Germline APC mutation (present in all cells) 2. **Promotion:** Polyp formation via Wnt pathway activation 3. **Progression:** Additional somatic mutations (KRAS, TP53) in individual polyps lead to malignant transformation APC loss is the **initiating event** in FAP; subsequent mutations are required for progression to cancer. ## Why Option 0 is Correct This option correctly identifies the molecular mechanism: APC loss → unopposed Wnt/β-catenin signaling → constitutive activation of TCF/LEF-dependent oncogenic transcription factors → polyp formation and cancer risk. This is the canonical pathway in FAP pathogenesis. **Mnemonic: "APC = Adenoma Prevention (when functional) / Adenoma Promotion (when mutated)"** — APC normally acts as a brake on Wnt signaling; loss of APC removes the brake.