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Mnemonic

Colorectal Adenoma to Carcinoma Sequence

A memory aid for the molecular steps from normal colon to carcinoma.

Pathology Gastrointestinal and Hepatic Pathology
Expansion

APC, then KRAS, then p53, accumulating over years

Mnemonic

“APC, KRAS, p53”, the order of mutations from normal mucosa to carcinoma:

  1. APC loss - normal epithelium to adenoma. The gatekeeper, and the gene mutated in familial adenomatous polyposis
  2. KRAS activation - adenoma growth and progression
  3. p53 loss, with 18q (DCC/SMAD4) - adenoma to carcinoma

“A K P”, in alphabetical order, is the sequence.

The whole process takes roughly 10 years, which is what makes screening effective: removing an adenoma at colonoscopy interrupts the sequence before carcinoma develops, and it is why the screening interval can be as long as it is.

Risk of malignancy in a polyp rises with size (over 1 cm), villous architecture and dysplasia, so a small tubular adenoma is far lower risk than a large villous one.

The alternative pathway is microsatellite instability from mismatch repair failure, which underlies Lynch syndrome, tends to be right sided, progresses faster, and predicts response to immunotherapy.

Expansion

Chromosomal instability pathway (about 80 per cent)

  1. APC loss: normal mucosa to hyperproliferative epithelium and small adenoma. Also the germline defect in familial adenomatous polyposis
  2. KRAS activation: adenoma enlarges
  3. p53 loss and additional mutations: carcinoma

The process takes 10 to 15 years, which is why removing adenomas at colonoscopy prevents cancer and why screening intervals are set as they are.

Microsatellite instability pathway (about 15 per cent)

  • Defective mismatch repair genes (MLH1, MSH2)
  • Germline in Lynch syndrome, sporadic through MLH1 hypermethylation
  • Tends to be right sided, mucinous, with better prognosis, and importantly it predicts response to immune checkpoint inhibitors

Adenoma risk factors for malignancy: size over 1 cm, villous rather than tubular architecture, and high grade dysplasia.

Familial adenomatous polyposis involves hundreds of polyps with essentially 100 per cent lifetime risk, requiring prophylactic colectomy, whereas Lynch syndrome produces few polyps but rapid progression, requiring frequent surveillance.