Multistep carcinogenesis: the adenoma–carcinoma sequence !
- Process
Cancer is not one mutation but several, gained over years. Colon cancer shows it best: normal mucosa, then a polyp, then cancer.
Updated 2026-11-01
What it is
Malignant transformation needs the accumulation of several genetic and epigenetic changes, each giving a growth advantage to a subclone. The colorectal adenoma-carcinoma sequence is the model: APC loss starts an adenoma, KRAS mutation helps it grow, and loss of SMAD4 and TP53 lets it become invasive carcinoma. The same logic underlies the gastric cascade linked to H. pylori and the progression of HPV-related cervical lesions.
Step by step
- Normal colonic mucosa: a cell loses both copies of APC (or inherits one defective copy in familial adenomatous polyposis).
- Beta-catenin accumulates and WNT signalling drives proliferation: an early adenoma forms.
- A KRAS mutation adds a growth advantage: the adenoma enlarges.
- Loss of 18q (SMAD4, SMAD2) removes TGF-beta growth inhibition: an advanced adenoma with high-grade dysplasia.
- Loss of TP53 removes the last checkpoint: invasive carcinoma.
- Further mutations and chromosomal instability allow metastasis.
Multistep cascades to know
| Organ | Sequence of lesions | Main drivers |
|---|---|---|
| Colon (chromosomal instability) | Normal → adenoma → advanced adenoma → carcinoma | APC, KRAS, SMAD4, TP53 |
| Colon (mismatch repair) | Normal → adenoma or serrated lesion → carcinoma with microsatellite instability | MLH1 and other MMR genes, BRAF |
| Stomach (intestinal type) | H. pylori gastritis → atrophy → intestinal metaplasia → dysplasia → carcinoma | Chronic inflammation, diet, host factors |
| Oesophagus | Reflux → Barrett metaplasia → dysplasia → adenocarcinoma | TP53, chromosomal instability |
| Cervix | HPV infection → CIN 1 → CIN 2-3 → invasive carcinoma | HPV E6 and E7, host mutations |
Clinical notes
- Removing adenomas at colonoscopy interrupts the sequence and prevents cancer.
- Colombia has a high rate of gastric cancer, especially in Andean regions; the gastric cascade was described by the Colombian pathologist Pelayo Correa.
- Chronic ulcerative colitis gives cancer through a dysplasia pathway that is less dependent on polyps, so surveillance looks for flat dysplasia.
Test yourself
Think of the answer, then tap the question to see it.
Which gene is usually lost first in the colorectal adenoma-carcinoma sequence?
APC, which allows beta-catenin to accumulate and drive proliferation.
Which change typically marks the transition from adenoma to carcinoma?
Loss of TP53, late in the sequence.
Which features of an adenoma raise its cancer risk?
Large size, villous architecture and high-grade dysplasia.
What are the steps of the gastric (Correa) cascade?
Chronic H. pylori gastritis, atrophic gastritis, intestinal metaplasia, dysplasia and intestinal-type adenocarcinoma.
Related
- Oncogenes: RAS, MYC, HER2, BCR-ABL and the table to know
- Tumour suppressor genes: RB, TP53, APC, BRCA and the two-hit hypothesis
- Genomic instability: mismatch repair, BRCA and xeroderma pigmentosum
- Dysplasia and carcinoma in situ
- Precancerous conditions: when chronic inflammation, metaplasia or hyperplasia raise the risk
- Metaplasia
- Chemical carcinogens: initiation, promotion and the table to know
- Oncogenic viruses and H. pylori: the table to know
Related conditions
- Colorectal cancer
- Colorectal polyps and hereditary polyposis syndromes (FAP, Lynch)
- Lynch syndrome (hereditary non-polyposis colorectal cancer)
- Gastric cancer
- Helicobacter pylori gastritis
- Barrett oesophagus
- Oesophageal cancer
- Cervical intraepithelial neoplasia (cervical dysplasia)
- Cervical cancer
- Ulcerative colitis
Elsewhere in DurgiPedia
- Large intestine, appendix and anal canal
- Stomach: gastric glands, parietal and chief cells
- Oncogenes and tumour suppressor genes
Microorganisms
Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.
Sources: APC gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); KRAS gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Colorectal Cancer Screening (StatPearls (NCBI Bookshelf), 2026); Gastric Cancer (StatPearls (NCBI Bookshelf), 2026).
Spotted a mistake?We are always improving for the community. Tell us what is wrong and our team will review it.Report a mistake
Representative model, for educational purposes only.