## Molecular Pathogenesis of Colorectal Carcinoma **Key Point:** The adenoma-carcinoma sequence is the dominant model of CRC development, with a well-characterized order of molecular events. ### The Classical Adenoma-Carcinoma Sequence The Fearon-Vogelstein model describes the typical progression: 1. **APC mutation** (early/initiating event) → loss of Wnt pathway inhibition → adenoma formation 2. **KRAS mutation** (intermediate event) → adenoma growth and progression 3. **TP53 mutation** (late event) → malignant transformation to carcinoma **High-Yield:** TP53 is a *late* event in CRC pathogenesis, not an early one. It occurs *after* adenoma formation and is associated with the transition to invasive carcinoma. Early TP53 mutations are NOT typical of the adenoma-carcinoma sequence. ### Alternative Pathways | Pathway | Key Feature | Gene(s) Involved | |---------|-------------|------------------| | **Chromosomal Instability (CIN)** | ~85% of sporadic CRC; aneuploidy | APC, KRAS, TP53 | | **Microsatellite Instability (MSI)** | ~15% of CRC; mismatch repair defects | MLH1, MSH2, MSH6, PMS2 | | **CpG Island Methylator Phenotype (CIMP)** | Epigenetic silencing | MLH1 (promoter methylation) | **Clinical Pearl:** Lynch syndrome (hereditary non-polyposis CRC) is caused by germline MMR gene mutations, leading to MSI and early-onset CRC, often without a polyposis phenotype. ### Why the Other Options Are Correct - **APC mutation** → initiates the adenoma-carcinoma sequence by activating Wnt signaling ✓ - **MSI/MMR defects** → hallmark of Lynch syndrome and a distinct CRC pathway ✓ - **KRAS mutation** → intermediate event promoting adenoma growth ✓ [cite:Robbins 10e Ch 17]
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