Oncogenes vs tumour suppressor genes: one hit or two
Oncogenes switch on with a single gain-of-function hit. Tumour suppressor genes classically must lose both copies. Knudson's two-hit hypothesis explains why the same gene can cause early or late tumours.
Chapters (12)
Contrast oncogenes (gain of function, dominant, one hit) with tumour suppressor genes (loss of function, both copies lost, two hits) using classic examples (RAS, MYC, BCR-ABL, HER2; RB1, TP53, APC), and apply Knudson's two-hit hypothesis to inherited versus sporadic tumours.
The short version
- Oncogenes are gain of function and dominant: one altered copy is enough (RAS, MYC, BCR-ABL, HER2).
- Tumour suppressors are loss of function and, classically, need two hits: both copies lost (RB1, p53, APC).
- A germline first hit means early, multiple and bilateral tumours; a sporadic tumour needs both hits in one cell.
- Inheritance looks dominant in a family, yet the gene works recessively inside each cell.
- The second hit is often a loss of heterozygosity: the normal copy is lost or copied over.
Oncogenes vs tumour suppressor genes: two children, one cancer gene
A one-year-old has a white glow in the pupil of both eyes. A two-year-old has the same cancer, retinoblastoma, in one eye only. The gene is the same and the tumour is the same, so why is one early and bilateral and the other later and unilateral?
The answer separates the two classes of cancer gene. Oncogenes need one hit. Tumour suppressor genes need two. The hook ages are typical medians: about 1 year for bilateral disease and about 2 years for unilateral.[6]
Go and stop: proto-oncogenes and tumour suppressors
A cell divides when growth signals say go and checkpoints say stop.[1][2]
The genes for go are proto-oncogenes, the accelerator. The genes for stop are tumour suppressors, the brakes.[2][3]
A proto-oncogene is a normal gene. Mutated or overexpressed, it becomes an oncogene: an accelerator stuck down.[2][3]
Oncogenes: gain of function, dominant, one hit
An oncogene is a gain of function, and it acts dominantly: one altered copy is enough.[3][13][14]
There are three ways to switch one on.
| Mechanism | Example | What happens |
|---|---|---|
| Point mutation | RAS | Mutant RAS stays locked in its active, GTP-bound form[7][8] |
| Translocation | MYC in Burkitt lymphoma | MYC moves beside an immunoglobulin enhancer[9] |
| Translocation | BCR-ABL in CML | BCR fuses to ABL[10] |
| Amplification | HER2 in some breast cancers | Extra copies of the gene[11] |
Tumour suppressor genes and Knudson's two-hit hypothesis
A tumour suppressor is a loss of function, and classically both copies must be lost, because one normal copy still makes enough protein.[3][4]
That is Knudson's two-hit hypothesis, formulated from retinoblastoma.[5][4][6]
| Oncogene | Tumour suppressor | |
|---|---|---|
| Change in function | Gain | Loss |
| Copies affected | One altered copy is enough | Both copies lost (classically) |
| Hits needed | One | Two |
| Role in the cell cycle | Accelerator stuck down | Brake removed |
| Examples | RAS, MYC, BCR-ABL, HER2 | RB1, p53, APC |
- RB1 was the first tumour suppressor discovered. Its protein, Rb, holds the cell at the G1 checkpoint.[6][4][1]
- p53 halts the cycle when DNA is damaged, and TP53 is the most commonly mutated gene in human cancer.[2][12]
- APC switches the Wnt pathway off by promoting the degradation of beta-catenin. Its loss gives colon polyps.[16][17]
Inherited vs sporadic: why the first hit decides the age
In the first child, a germline mutation, inherited or new, means every retinal cell already carries one hit. One more hit, in any of millions of cells, is enough, so tumours come early, in both eyes.[6][4][5]
In the second child, both hits had to strike one cell by chance. That is rare, so the tumour comes later and on one side only.[6][4]
| Germline first hit | Sporadic | |
|---|---|---|
| First hit | In every cell | Chance event in one cell |
| Second hit | Any one of millions of cells | Must hit the same cell |
| Typical pattern | Early, bilateral | Later, one eye |
A made-up example shows the arithmetic. The numbers are invented for illustration and are not real mutation rates.
Made-up odds: why the inherited form comes early
Suppose a retina has ten million cells, and any cell has a one in a million chance of losing a given copy.
- Inherited: 10⁷ cells × 10⁻⁶ = about 10 cells with the second hit, so about ten tumours are expected
- Sporadic: one cell needs two hits, 10⁻⁶ × 10⁻⁶ = 10⁻¹² per cell
- Across ten million cells: 10⁻¹² × 10⁷ = 10⁻⁵, about one in a hundred thousand
The inherited route is vastly more likely, which is why those tumours arrive early and in more than one place.
Dominant in the family, recessive in the cell: loss of heterozygosity
Inheritance looks dominant in a family, yet the gene works recessively inside each cell: one inherited mutant copy predisposes, but function is lost only when the second copy goes.[5][3][6]
The second hit is often a loss of heterozygosity: the normal copy is lost or copied over.[4][16][3]
Practice question
Original · USMLE styleA 19-year-old man has a screening colonoscopy because his father underwent colectomy for colon cancer at a young age. The examination shows hundreds of adenomatous polyps throughout the colon. Genetic testing of peripheral blood leukocytes identifies a heterozygous truncating mutation in the APC gene.
Common questions
What is the difference between an oncogene and a tumour suppressor gene?
An oncogene is a gain of function that acts dominantly, so one altered copy is enough. A tumour suppressor is a loss of function, and classically both copies must be lost.
What is Knudson's two-hit hypothesis?
It states that both copies of a tumour suppressor gene must be inactivated for a tumour to form. It was formulated from retinoblastoma.
Why is inherited retinoblastoma earlier and bilateral?
A germline mutation puts the first hit in every retinal cell, so one more hit in any of millions of cells is enough. The sporadic form needs both hits in one cell, so it is rarer, later and one-sided.
What is loss of heterozygosity?
It is a common second hit in which the normal copy of the gene is lost or copied over.
Which genes are classic oncogenes and tumour suppressors?
Classic oncogenes are RAS, MYC, BCR-ABL and HER2. Classic tumour suppressors are RB1, p53 and APC.
Transcript
Read the full narration, by chapter664 words
0:00Two children, one cancer gene
A 1-year-old has a white glow in the pupil of both eyes. A 2-year-old has the same cancer, retinoblastoma, in one eye only. Same gene, same tumour. Why is one early and bilateral, the other later and unilateral?
0:17Go and stop: proto-oncogenes and tumour suppressors
Today: contrast oncogenes, which need one hit, with tumour suppressor genes, which need two. A cell divides when growth signals say go and checkpoints say stop. The genes for go are proto-oncogenes, the accelerator. The genes for stop are tumour suppressors, the brakes.
0:37Oncogene: gain of function, dominant, one hit
A proto-oncogene is a normal gene. Mutated or overexpressed, it becomes an oncogene: an accelerator stuck down. An oncogene is a gain of function, and it acts dominantly: one altered copy is enough.
0:52Three ways to switch one on: RAS, MYC and BCR-ABL, HER2
Three ways to switch one on. A point mutation: mutant RAS stays locked in its active, GTP bound form. A translocation: in Burkitt lymphoma, MYC moves beside an immunoglobulin enhancer, and in CML, BCR fuses to ABL. An amplification: extra copies of HER2 in some breast cancers.
1:18Tumour suppressor: both copies lost, Knudson's two hits
A tumour suppressor is a loss of function, and both copies must be lost, because one normal copy still makes enough protein. That is Knudson's two-hit hypothesis.
1:30RB1, p53 and APC
The classic is RB one, the first tumour suppressor discovered. Its protein, Rb, holds the cell at the G one checkpoint. Then p53, which halts the cycle when DNA is damaged, and is the most commonly mutated gene in human cancer. And APC, which switches the Wnt pathway off by degrading beta catenin; its loss gives colon polyps.
1:56Our two children: inherited vs sporadic first hit
Our two children. In the first, a germline mutation, inherited or new, means every retinal cell already carries one hit. One more hit, in any of millions of cells, is enough: tumours come early, in both eyes. In the second, both hits had to strike one cell by chance: rare, later, one-sided.
2:20Made-up odds: why the inherited form comes early
Made-up odds: a retina has 10 million cells, and any cell has a one in a million chance of losing a given copy. Inherited: 10 million cells each need one hit, so about 10 tumours are expected. Sporadic: one cell needs two hits, one in a million times one in a million, across 10 million cells: about one in 100,000.
2:45Dominant in the family, recessive in the cell, LOH
That is why inheritance looks dominant in a family, yet the gene works recessively inside each cell. The second hit is often a loss of heterozygosity: the normal copy is lost or copied over.
3:00Your turn: a practice question
Your turn. A 19-year-old man has hundreds of adenomatous polyps at colonoscopy, and his father had a colectomy for colon cancer at a young age. Blood testing finds a heterozygous truncating APC mutation. Which best explains how the polyps developed? A, a gain-of-function change in the mutant APC allele in every colonic cell. B, two independent acquired APC mutations in one colonic cell, with no inherited contribution. C, acquired loss of the remaining normal APC allele in individual colonic epithelial cells. D, translocation of APC beside an immunoglobulin enhancer in colonic epithelial cells. E, inherited loss of both APC alleles in every colonic cell. Pause here and decide.
3:58The answer, one option at a time
A is out: APC is a tumour suppressor, so its mutations cause loss of function. B is out: two acquired hits is the sporadic route; he already carries the first hit in every cell. D is out: a translocation that overexpresses a gene is how an oncogene such as MYC is switched on. E is out: his mutation is heterozygous, so every cell still has a normal copy until it is lost. So the answer is C. The first hit is in every colonic cell, so one acquired hit in any cell leaves it with no working APC, and a polyp starts, many times over.
4:41Recap pocket card
Three things to keep. One: oncogenes are gain of function, dominant, one hit: RAS, MYC, BCRABL, HER2. Two: tumour suppressors are loss of function, classically needing two hits: RB1, p53, APC. Three: a germline first hit means early, multiple and bilateral tumours; a sporadic one needs both hits in one cell. Keep these points, and try the question again.
Sources
Numbers in the text, e.g. [1], point here- OpenStax Biology 2e, 10.3 Control of the Cell Cycle. openstax.org/books/biology-2e/pages/10-3-control-of-the-cell-cycle
- OpenStax Biology 2e, 10.4 Cancer and the Cell Cycle. openstax.org/books/biology-2e/pages/10-4-cancer-and-the-cell-cycle
- Oncogenes and tumor suppressor genes: functions and roles in cancers, 2024. europepmc.org/article/PMC/PMC11141506
- The RB1 story: characterization and cloning of the first tumor suppressor gene, Genes 2019. europepmc.org/article/PMC/PMC6895859
- Mourning Dr. Alfred G. Knudson: the two-hit hypothesis, Cancer Sci 2017. europepmc.org/article/PMC/PMC5276834
- Retinoblastoma: present scenario and future challenges, 2023. europepmc.org/article/PMC/PMC10478474
- Kirsten Ras oncogene: significance of its discovery in human cancer research, 2016. europepmc.org/article/PMC/PMC5216832
- A comparative analysis of individual RAS mutations in cancer biology, 2019. europepmc.org/article/PMC/PMC6813200
- Cryptic MYC insertions in Burkitt lymphoma, 2022. europepmc.org/article/PMC/PMC8846522
- CML from the Philadelphia chromosome to specific target drugs, 2021. europepmc.org/article/PMC/PMC7918527
- HER2 gene amplification testing by FISH, J Clin Oncol 2016. europepmc.org/article/PMC/PMC5074347
- Mutational processes shape the landscape of TP53 mutations in human cancer, 2018. europepmc.org/article/PMC/PMC6168352
- The epigenetic reader MeCP2 is an emerging oncogene in cancer biology, 2023. europepmc.org/article/PMC/PMC10216337
- X chromosome inactivation, X-linked disorders, and cancer, 2026. europepmc.org/article/PMC/PMC13171066
- Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes, Eur J Hum Genet 2020. europepmc.org/article/PMC/PMC7609280
- The genetic basis of familial adenomatous polyposis, 2015. europepmc.org/article/PMC/PMC4404874
- Familial adenomatous polyposis, 2009. europepmc.org/article/PMC/PMC2772987
The hook patients are invented teaching vignettes. The worked example uses made-up numbers: ten million cells and one chance in a million per cell; they are not real mutation rates.
The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.
Image credits. Illustrations: Servier Medical Art (smart.servier.com), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), adapted (recoloured, outlined, resized): two baby figures, mitosis cycle, colon with polyps, young man. Normal-cell and cancerous-cell icons by Servier via Bioicons (bioicons.com), CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/), adapted. The eyes, chromosomes, pedals, switch, cell grids, pedigree, question card, pocket card and all handwriting are drawn in code (original). No AI-generated teaching images.
Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-HEME-008.
For exam study only, not medical advice. Read the medical disclaimer.
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