1. Chromosomal instability (APC/beta-catenin) pathway (~80% of sporadic cases)
Underlies the classic adenoma-carcinoma sequence
Sequential accumulation of mutations: APC gene inactivation (early event, initiates adenoma formation) → KRAS mutation (promotes growth of the adenoma) → loss of tumour suppressor genes (e.g., SMAD4, and later TP53, associated with progression to carcinoma)
Due to inactivation of DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2), either sporadically (MLH1 promoter hypermethylation) or as part of Lynch syndrome (germline mutation)
Leads to accumulation of mutations in microsatellite repeat sequences throughout the genome, including in genes regulating cell growth
Adenoma-carcinoma sequence (detailed)
Normal colonic epithelium → APC gene mutation (both alleles) → formation of a small adenomatous polyp (aberrant crypt focus → early adenoma)
Loss of chromosome 18q (SMAD2/SMAD4) → adenoma progresses further
TP53 mutation/loss (late event) → progression from adenoma to invasive carcinoma
This stepwise accumulation of genetic alterations (typically taking many years) provides the biological basis for colorectal cancer screening programs (colonoscopy with polypectomy), which interrupt this sequence by removing adenomas before malignant transformation occurs
