Alfred Knudson proposes the two-hit hypothesis

Historical milestone — this page describes an event dated 1971. It is not current breaking news.

An idea built from arithmetic

In April 1971, Alfred G. Knudson Jr. published "Mutation and cancer: statistical study of retinoblastoma" in the Proceedings of the National Academy of Sciences, volume 68, pages 820 to 823.

He had no way to read DNA. Gene sequencing did not yet exist in any usable form. What he had was 48 children with retinoblastoma, a cancer of the retina, and their records: the age each was diagnosed, and whether one eye or both were affected.

From that, he worked out how cancer starts. The paper is a good argument for the idea that a careful question beats a fancy instrument.

The pattern in the numbers

Two things about retinoblastoma had long looked odd together.

Some children develop tumors in both eyes, and they tend to be diagnosed young. Others develop a tumor in one eye only, and tend to be older when it appears. NCI still describes this relationship today: children with disease in both eyes usually present within the first 12 months of life.

Knudson tested whether one mechanism could produce both patterns. Using Poisson statistics — the math for counting rare, independent events — he found the numbers only fit if two separate mutations were needed to start a tumor.

What "two hits" means

Every cell carries two copies of most genes, one from each parent. Knudson's model says a retinoblastoma needs both copies of a particular gene knocked out.

In the inherited form, a child is born with one copy already faulty in every cell of the body. Only one more event is needed, and there are millions of retinal cells for it to happen in. So tumors appear early, and often in both eyes.

In the non-inherited form, both events have to occur by chance in the same single cell. That is far less likely, so it takes longer and almost always affects one eye.

The paper calculates that a child carrying the first mutation develops an average of three retinoblastomas. That single number explains the whole spread of what doctors saw: occasional carriers with no tumor at all, carriers with one eye affected, carriers with both, and children with several tumors in one eye.

Why it mattered beyond one rare cancer

The two-hit model gave cancer research a testable prediction: there should be a specific gene whose loss causes this disease.

That gene, later named RB1, was isolated in 1986. Knudson's inference held up. More broadly, the model established the idea of the tumor suppressor gene — a gene whose job is to restrain cell division, where cancer follows from losing function rather than gaining it.

It also explained something families had noticed for generations. Inherited cancer risk is not a cancer you are born with. It is a head start that the disease has, and it shifts the odds and the timing rather than guaranteeing the outcome. Our page on genetic testing for cancer risk covers what that means for testing today.

The disease itself

Retinoblastoma is rare. NCI puts it at about 3% of cancers in children under 15, with roughly 3 cases per million children under 20 each year. Among children aged 0 to 4 the rate is 18.4 per million. Two-thirds of cases are diagnosed before age 2.

Diagnosis is usually made without a biopsy, because taking tissue from inside an eye risks spreading the tumor. Instead a specialist examines the fully dilated eye under anesthesia and maps every tumor. Ultrasound and MRI show whether the disease extends beyond the eye. Treatment aims both to save the child's life and to preserve vision where that is possible. Our retinoblastoma page sets out the treatment options in more detail.

Signs that need an eye examination

Retinoblastoma is usually spotted by a parent, not a screening program:

• A pupil that looks white or cloudy rather than showing the normal red reflex in a flash photograph. NCI notes this is the most common presenting sign, and photographs are often where it is first seen.
• An eye that turns in or out, which is the second most common sign.
• Eye pain, redness, persistent swelling, or an eye that looks enlarged.
• A child who seems not to see on one side, or whose vision has clearly changed.

None of these should wait for a routine checkup. All of them warrant an appointment with someone who can dilate the pupil and examine the retina.

What this study cannot tell you

• Knudson worked entirely from statistics on 48 children. He inferred a gene; he did not find one. RB1 was not isolated until 15 years later.
• The tidy "two hits and you are done" picture has been refined since. Most adult cancers involve far more than two genetic changes, accumulated over decades.
• The model fits childhood tumor suppressor cancers like retinoblastoma best. It is not a general account of how every cancer begins.
• Carrying an inherited mutation shifts risk. It does not determine what will happen to any individual child.
• This page summarizes a historical event. It is not medical advice, and it is not guidance on whether a particular family should seek testing.

Sources

This article was written from the sources below, which were checked on the source-check date shown above.

• Knudson AG, "Mutation and cancer: statistical study of retinoblastoma," Proceedings of the National Academy of Sciences 1971;68(4):820-3 (PMID 5279523): https://pubmed.ncbi.nlm.nih.gov/5279523/
• National Cancer Institute, Retinoblastoma Treatment (PDQ), health professional version: https://www.cancer.gov/types/retinoblastoma/hp/retinoblastoma-treatment-pdq
• National Cancer Institute, Childhood Cancers: https://www.cancer.gov/types/childhood-cancers

How this page was made

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. It is not a diagnostic service, does not recommend treatments, and is not for emergencies.

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