Bert Vogelstein maps a genetic model of colorectal cancer

Historical milestone — this page describes an event dated 1988. It is not current breaking news.

The idea before the evidence

By the 1980s researchers suspected that cancer was not a single event. Something more like a sequence: a cell picks up one fault, then another, and only after several does it become malignant.

Colorectal cancer was the natural place to test that, for a practical reason. Most bowel cancers grow out of adenomas, benign polyps that surgeons remove routinely. That means the whole progression can be sampled. You can hold an early polyp, a large polyp and a cancer in your hand and compare their DNA.

That is what Bert Vogelstein's group at Johns Hopkins did.

What they measured

The 1988 paper in the New England Journal of Medicine examined 172 colorectal tumor specimens across the range of development.

They looked for four specific genetic changes: mutations in the ras gene, and loss of DNA from chromosomes 5, 17 and 18. Then they asked which changes appeared at which stage.

The pattern was orderly.

• ras mutations appeared in 9% of adenomas smaller than 1 cm, 58% of adenomas larger than 1 cm, and 47% of carcinomas.
• Chromosome 18 loss appeared in 11% to 13% of early adenomas, 47% of advanced adenomas, and 73% of carcinomas.
• Chromosome 17p loss was found almost only in carcinomas, at 75%.
• Chromosome 5 loss, in the region linked to familial adenomatous polyposis, occurred in 29% to 35% of adenomas and carcinomas from people without that inherited condition.

The four faults accumulated in a way that tracked the clinical progression of the tumors. The authors concluded that becoming cancerous typically required switching on an oncogene, a gene that pushes growth, alongside losing several tumor suppressor genes, which normally hold growth back.

In 1990, Eric Fearon and Vogelstein set this out as a formal map in Cell, and it has been known as the adenoma-carcinoma sequence ever since.

Why the model still shapes care

The practical consequence is the reason colonoscopy exists in the form it does.

If cancer arrives in one step, screening can only find it after the fact. If it arrives over years through a visible intermediate, you can interrupt it. Removing an adenoma removes the cancer it might have become, a decade before it would have appeared.

That is prevention, not early detection, and it is unusual. Most screening finds cancer sooner. Colonoscopy can stop it starting. Our guide to colorectal cancer screening covers the tests available.

NCI lists the main screening methods as fecal occult blood testing, DNA stool testing, sigmoidoscopy, colonoscopy and virtual colonoscopy. It also notes that a digital rectal exam has not been shown to reduce deaths from the disease.

The numbers today

The American Cancer Society expects 158,850 new US colorectal cancer diagnoses and 55,230 deaths in 2026. Five-year relative survival across all stages, for cases diagnosed in 2016 to 2022, is 65.4%.

Stage tells most of the story. Localized disease carries 91.3% five-year relative survival. Regional disease, in nearby lymph nodes, carries 75.2%. Distant disease carries 16.9%. Only 34% of US cases are caught while localized, and 23% are already distant. Those stage figures track the same 2016 to 2022 diagnoses.

That gap between 91.3% and 16.9% is what a screening program is buying. These are group figures over past years and do not forecast any individual's course. Our page on colorectal cancer covers types and treatment.

When to get checked

Screening is for people without symptoms. If any of these appear, they need attention regardless of when the last screening was. NCI lists:

• Blood in the stool, either bright red or very dark
• A change in bowel habits, including diarrhea or constipation
• A feeling that the bowel does not empty completely
• Stools that are narrower or a different shape than usual
• General abdominal discomfort: frequent gas pains, bloating, or fullness

Add unexplained weight loss and unexplained iron-deficiency anemia, both of which often bring people to a colonoscopy. Any of these lasting more than three weeks deserves an appointment.

What this does not mean

• The model describes a common route, not the only one. Some colorectal cancers arise through different pathways, including mismatch repair defects and inflammatory bowel disease.
• The specific percentages come from tumor specimens collected in the 1980s at one center. The ordering held up; the exact figures are historical.
• Most adenomas never become cancer. Finding one is not a diagnosis of cancer, and removing it is often the end of the matter.
• A stepwise model does not give a timetable. Progression is measured in years and varies widely between people.
• Nothing here is a substitute for a screening recommendation from your own clinician, whose advice depends on your age, family history and prior findings.

Sources

• New England Journal of Medicine (record via PubMed), Genetic Alterations during Colorectal-Tumor Development — https://pubmed.ncbi.nlm.nih.gov/2841597/
• Cell (record via PubMed), A genetic model for colorectal tumorigenesis — https://pubmed.ncbi.nlm.nih.gov/2188735/
• NCI PDQ, Colorectal Cancer Screening (Patient Version) — https://www.cancer.gov/types/colorectal/patient/colorectal-screening-pdq
• NCI PDQ, Colon Cancer Treatment (Patient Version) — https://www.cancer.gov/types/colorectal/patient/colon-treatment-pdq
• SEER Cancer Stat Facts, Colorectal Cancer — https://seer.cancer.gov/statfacts/html/colorect.html

How this article was prepared

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

The National Cancer Information Foundation publishes Cancer Explained. This page is for learning. It is not medical advice and does not suggest a test or treatment.

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