## The Adenoma-Carcinoma Sequence **Key Point:** The adenoma-carcinoma sequence is a well-established multi-step model of colorectal carcinogenesis, with APC mutation as the initiating event. ### Sequential Genetic Alterations | Stage | Genetic Event | Morphology | |-------|---------------|------------| | Normal epithelium | — | Normal mucosa | | Early adenoma | APC mutation | Small adenoma (<1 cm) | | Intermediate adenoma | KRAS activation | Larger adenoma (1–2 cm) | | Late adenoma | TP53 loss | Large adenoma (>2 cm) | | Carcinoma | SMAD4 loss | Invasive cancer | **High-Yield:** APC (Adenomatous Polyposis Coli) inactivation is the **first hit** in sporadic colorectal cancer and is present in ~80% of colorectal adenomas. Loss of APC function removes the "brake" on Wnt/β-catenin signalling, leading to uncontrolled cell proliferation and adenoma formation. **Clinical Pearl:** Familial Adenomatous Polyposis (FAP) patients inherit a germline APC mutation and develop hundreds to thousands of adenomas by age 30–40, with near 100% risk of colorectal cancer if untreated. **Mnemonic:** **A-K-P-S** = **A**PC → **K**RAS → **P**53 → **S**MAD4 (the order of genetic hits in the adenoma-carcinoma sequence). ### Why APC is the Initiator 1. Present in nearly all adenomas, even tiny ones 2. Sufficient alone to initiate adenoma formation (proven in APC knockout mouse models) 3. KRAS, TP53, and SMAD4 mutations occur later and drive progression to malignancy [cite:Robbins 10e Ch 17]
Sign up free to access AI-powered MCQ practice with detailed explanations and adaptive learning.