A 35-year-old man from Mumbai presents with a 2-year history of multiple colorectal polyps detected on colonoscopy. Histology shows adenomatous polyps. His father died of colorectal cancer at age 52, and his paternal grandfather had gastric cancer. Genetic testing reveals a heterozygous germline mutation in the APC gene. Which of the following best describes the molecular mechanism by which loss of APC function drives adenoma formation in this patient?

Explanation

## APC and Wnt/β-Catenin Signaling in Colorectal Tumorigenesis ### Normal APC Function **Key Point:** APC is a **negative regulator of Wnt/β-catenin signaling**. It forms part of the "destruction complex" that targets β-catenin for proteasomal degradation. ### The Destruction Complex - **Components:** APC, Axin, GSK-3β, CK1 - **Function:** Phosphorylates β-catenin → ubiquitination → proteasomal degradation - **Result:** Low cytoplasmic β-catenin levels in the absence of Wnt signaling ### Mechanism of Adenoma Formation (Loss of APC) ```mermaid flowchart TD A[Normal APC present]:::outcome --> B[Destruction complex active] B --> C[β-catenin phosphorylated and degraded] C --> D[Low cytoplasmic β-catenin] D --> E[β-catenin cannot bind TCF/LEF]:::outcome E --> F[Wnt target genes OFF] F --> G[Normal cell growth]:::outcome H[APC mutation/loss]:::urgent --> I[Destruction complex inactive] I --> J[β-catenin accumulates] J --> K[High cytoplasmic β-catenin] K --> L[β-catenin binds TCF/LEF]:::decision L --> M[Wnt target genes ON] M --> N[c-MYC, Cyclin D1 upregulation]:::action N --> O[Uncontrolled proliferation]:::urgent O --> P[Adenoma formation]:::outcome ``` ### Wnt Target Genes Activated - **c-MYC** → cell proliferation - **Cyclin D1** → G1/S transition - **Survivin** → anti-apoptosis - **VEGF** → angiogenesis **High-Yield:** APC mutations occur in ~80% of sporadic colorectal cancers and 100% of familial adenomatous polyposis (FAP) cases. This is the **initiating event** in the adenoma-carcinoma sequence. ### Clinical Correlation: Familial Adenomatous Polyposis (FAP) - **Germline APC mutation** → heterozygous carriers - **Phenotype:** Hundreds to thousands of adenomatous polyps by age 20–30 - **Progression:** Nearly 100% develop colorectal cancer by age 40–50 without prophylactic colectomy - **Extracolonic manifestations:** Gastric polyps, duodenal adenomas (as in this patient's grandfather), desmoid tumors, congenital hypertrophy of retinal pigment epithelium (CHRPE) **Clinical Pearl:** The patient's father's early-onset colorectal cancer (age 52) and paternal grandfather's gastric cancer are consistent with FAP-related extracolonic malignancies. Prophylactic colectomy is indicated. **Mnemonic: FAP Features** — **PACED** - **P**olyps (hundreds to thousands) - **A**denoma-carcinoma sequence - **C**olorectal cancer (nearly 100% if untreated) - **E**xtracolonic manifestations (gastric, duodenal, desmoid) - **D**ominant inheritance (autosomal) [cite:Robbins 10e Ch 7]