Paper II
Question
Aetiopathogenesis of carcinoma colon.
Answer
Risk factors
- Low-fibre, high animal fat diet; age; inflammatory bowel disease; hereditary syndromes (FAP, Lynch syndrome); obesity, smoking
Molecular pathways
1. Chromosomal instability (APC/beta-catenin) pathway (~80%)
- Underlies the classic adenoma-carcinoma sequence
- APC gene inactivation (initiates adenoma) → KRAS mutation (promotes growth) → loss of chromosome 18q/SMAD4 → TP53 mutation (progression to carcinoma)
2. Microsatellite instability pathway (~15%)
- Due to DNA mismatch repair gene inactivation (MLH1, MSH2, etc.), sporadically or as part of Lynch syndrome
- Leads to accumulated mutations in microsatellite repeat sequences
Adenoma-carcinoma sequence
- Normal epithelium → aberrant crypt focus → small adenoma → larger/villous adenoma → carcinoma in situ → invasive carcinoma, driven by the stepwise accumulation of the above genetic alterations over years, forming the biological rationale for colonoscopic screening/polypectomy