Oncogenes, Tumour Suppressors and Cancer

Cancer is a genetic disease of somatic cells. Its molecular causes are mutations that disrupt the normal control of the cell cycle, allowing cells to proliferate when they should not and to evade the mechanisms — apoptosis, replicative senescence, immune surveillance — that ordinarily eliminate aberrant cells. The two principal categories of cancer-driver gene are proto-oncogenes, whose activation produces gain-of-function mutants that accelerate proliferation, and tumour-suppressor genes, whose loss-of-function mutation removes the cellular brakes. Understanding the distinction, and the molecular logic that follows from it, is central to A* answers and is the source of one of the most persistent errors at A-Level: confusing the two gene classes.

Spec mapping: This lesson sits in AQA 7402 Section 3.8.3 — Gene expression and cancer. The specification expects candidates to describe the role of proto-oncogenes and tumour-suppressor genes in normal cells, to explain how mutations convert them to drivers of cancer, to relate hypermethylation of tumour-suppressor promoters to gene silencing, and to consider the molecular basis of targeted therapies. (Refer to the official AQA specification document for exact wording.)

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The Cell Cycle in Brief

Before considering cancer it helps to fix what cancer disrupts. The somatic cell cycle has four phases (G1, S, G2, M), regulated by cyclin–CDK complexes whose activity is gated by checkpoints. Two checkpoints are central to cancer biology:

• G1/S checkpoint ("restriction point") — the cell decides whether to commit to DNA replication. It assesses growth-factor signalling, nutrient status, cell size, and DNA integrity. The tumour suppressor RB1 holds this checkpoint closed; mitogenic signalling relieves the block.
• G2/M checkpoint — the cell assesses DNA replication fidelity before mitosis. The tumour suppressor TP53 (p53) is the central guardian here; in response to DNA damage it pauses the cycle, drives DNA repair, or — if damage is irreparable — triggers apoptosis.

Cancer arises when mutations push the cell through these checkpoints inappropriately or remove the safety mechanisms that arrest or eliminate damaged cells.

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Proto-oncogenes and Oncogenes

Key Definition: A proto-oncogene is a normal cellular gene whose protein product promotes cell division — examples include growth factors, growth-factor receptors, signal-transduction kinases, and transcription factors. A gain-of-function mutation converts a proto-oncogene into an oncogene, whose product is hyperactive or constitutively active, driving uncontrolled proliferation.

Gain-of-function — the key principle

Oncogenes are gain-of-function. The mutant protein does something the normal protein cannot: it signals constitutively (without the upstream cue), it signals more strongly than the normal protein, or it is produced at much higher levels than normal. One activating mutation is sufficient to produce the cancer-driving phenotype: oncogenes act dominantly at the cellular level — a mutation in one of the two alleles is enough.

Types of activating mutation

Mechanism	Effect on protein	Example
Point mutation	Single amino acid change locks protein in active conformation	RAS codon 12 (Gly → Val) abolishes GTP hydrolysis; RAS is permanently GTP-bound and signalling
Gene amplification	Many copies of the gene produced; protein over-expressed	HER2/ERBB2 amplification in ~20% of breast cancers; MYC amplification in neuroblastoma
Chromosomal translocation	Fusion gene produces hyperactive chimeric protein, or normal protein placed under aberrant control	BCR-ABL fusion (Philadelphia chromosome) in chronic myeloid leukaemia produces a constitutively active tyrosine kinase
Promoter / regulatory mutation	Normal protein expressed at much higher levels	MYC translocation to the immunoglobulin heavy chain locus in Burkitt lymphoma drives MYC over-expression

Canonical examples

• RAS (HRAS, KRAS, NRAS) — small GTPases that transduce signals from receptor tyrosine kinases to downstream proliferation pathways (Raf-MEK-ERK). Activating point mutations are found in ~30% of all human cancers; KRAS mutations are particularly common in pancreatic (~90%), colorectal (~40%) and lung adenocarcinomas (~25%).
• MYC — a transcription factor that drives the expression of genes for cell growth, ribosome biogenesis and metabolism. Amplification or translocation produces over-expression in many cancers (Burkitt lymphoma, neuroblastoma, breast cancer).
• HER2 (ERBB2) — a receptor tyrosine kinase on the cell surface. Gene amplification (a copy-number gain, not a point mutation) leads to over-expression and constitutive signalling. Drives a subset of breast cancers (~15–20%) and is the molecular target of trastuzumab (see below).

Exam Tip: "Gain-of-function" is the discriminating phrase for oncogenes. Use it explicitly. Show that you understand it means one mutated allele is enough, in contrast to tumour suppressors, where both alleles must be inactivated.

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Tumour-Suppressor Genes

Key Definition: A tumour-suppressor gene is a normal cellular gene whose product restrains cell proliferation, triggers cell-cycle arrest in response to damage, or drives apoptosis. Loss-of-function mutations in both alleles remove this restraint and contribute to cancer.

Loss-of-function — the key principle

Tumour suppressors are loss-of-function. The mutant allele produces a non-functional protein (or no protein at all), and at the cellular level the phenotype is recessive — one functional allele is generally sufficient to maintain the tumour-suppressing activity. Both alleles must be inactivated before the cell loses the suppression.

Mechanisms of inactivation

Tumour suppressors can be inactivated by:

• Point mutation producing a non-functional or destabilised protein.
• Deletion of part or all of the gene.
• Loss of heterozygosity (LOH) — loss of the chromosomal region containing the remaining wild-type allele, often by mitotic recombination or whole-chromosome non-disjunction.
• Promoter hypermethylation — epigenetic silencing of the gene (see Lesson 1). Many tumour suppressors (CDKN2A, MLH1, BRCA1) are silenced in cancers by promoter CpG-island methylation rather than by genetic mutation. The DNA sequence is intact; the gene is simply not transcribed.

Knudson's two-hit hypothesis

Alfred Knudson (1971), working on retinoblastoma, proposed a framework that has guided the field for half a century: a tumour suppressor must lose both of its two copies before the cell loses tumour-suppressing activity. (His framework is paraphrased here — no verbatim quotation from Knudson's papers is reproduced.)

The two-hit logic explains a striking clinical pattern:

• Familial retinoblastoma — affected individuals inherit one mutant RB1 allele from a parent. Every cell in their body already has one "hit". A single second somatic mutation in any retinal cell during development is then sufficient to inactivate RB1 in that cell, producing a tumour. Familial cases are therefore characteristically early-onset and bilateral (often both eyes).
• Sporadic retinoblastoma — affected individuals are born with two functional RB1 alleles. Two independent somatic mutations must occur in the same retinal cell. This is a much rarer event, so sporadic cases are typically later-onset and unilateral (one eye).

The two-hit hypothesis applies specifically to tumour suppressors. Oncogenes do not require two hits: a single activating mutation in one allele is sufficient.

Canonical examples

• TP53 (p53) — a transcription factor that responds to DNA damage by inducing cell-cycle arrest (via the CDK inhibitor p21), DNA repair, and — when damage is irreparable — apoptosis (via BAX and other proapoptotic targets). Sometimes informally described as a guardian of cellular genome integrity (the actual coined phrase comes from a review, paraphrased here without verbatim quotation). TP53 is mutated in approximately half of all human cancers, making it the single most frequently mutated tumour-suppressor gene.
• RB1 — encodes the retinoblastoma protein (pRb), which holds the G1/S checkpoint closed by binding the E2F transcription factor. Phosphorylation of pRb by cyclin-CDK releases E2F and licenses S-phase entry. Loss-of-function mutations in RB1 allow inappropriate S-phase entry — first identified in retinoblastoma and prototypical for the two-hit hypothesis.
• BRCA1, BRCA2 — encode proteins required for homologous recombination repair of DNA double-strand breaks. Loss-of-function mutations (not gain-of-function — BRCA1/2 are tumour suppressors, never oncogenes) substantially elevate lifetime risk of breast and ovarian cancer. Carriers are heterozygous in their germline; tumours typically show somatic loss of the second allele in the relevant tissue, consistent with the two-hit model.
• CDKN2A (p16INK4a) — encodes a CDK inhibitor that blocks cyclin D-CDK4/6, holding the G1/S checkpoint closed. Frequently inactivated in many cancers, often by promoter hypermethylation rather than genetic mutation.
• APC — a tumour suppressor lost early in colorectal carcinogenesis; loss promotes inappropriate Wnt signalling and crypt cell proliferation.

Exam Tip: "Loss-of-function" is the discriminating phrase for tumour suppressors. The two-hit hypothesis is the standard A-Level framework for explaining why familial cancer syndromes are dominantly inherited at the level of the organism but recessive at the level of the cell.

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Oncogenes vs Tumour Suppressors — Side by Side

Feature	Oncogene	Tumour suppressor
Normal function	Promote cell division (positive regulator)	Restrain cell division / drive apoptosis (negative regulator)
Type of mutation in cancer	Gain-of-function	Loss-of-function
Number of alleles that must be mutated	One is enough	Both must be inactivated (two-hit)
Cellular dominance	Dominant	Recessive (at the cellular level)
Inheritance pattern of familial cancers	Rare to inherit (a constitutive activating mutation is usually embryonic-lethal)	Common — one mutant allele inherited, second hit somatic
Mechanisms of activation/inactivation	Point mutation, amplification, translocation	Point mutation, deletion, LOH, promoter hypermethylation
Examples	RAS, MYC, HER2, BCR-ABL	TP53, RB1, BRCA1/2, CDKN2A, APC

Mermaid: the two-hit hypothesis

flowchart LR
  A["Familial case: 1 mutant TS allele inherited in every cell"] --> B["Second hit (somatic mutation) in any cell"]
  B --> C["Cell loses tumour suppression → tumour"]
  D["Sporadic case: 2 wild-type TS alleles at birth"] --> E["First hit (somatic) — cell still has 1 functional allele"]
  E --> F["Second hit (somatic) in same cell"]
  F --> G["Cell loses tumour suppression → tumour"]
  H["Compare: oncogene"] --> I["Single activating mutation in 1 allele"]
  I --> J["Cell drives uncontrolled proliferation"]

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Role of Methylation in Silencing Tumour Suppressors

DNA methylation, covered as a general mechanism in Lesson 1, plays a specific role in cancer: hypermethylation of tumour-suppressor promoters is a major mechanism of tumour-suppressor inactivation that does not involve any change to the DNA sequence.

• Promoter CpG islands in tumour suppressors such as CDKN2A, MLH1, BRCA1 and APC are typically unmethylated in normal cells (allowing transcription).
• In many cancers these CpG islands become heavily methylated. Methyl-CpG-binding proteins (e.g. MeCP2) recruit histone deacetylases and H3K9 methyltransferases, compacting the chromatin and silencing the gene.
• The DNA sequence is intact — sequencing would show wild-type — but the protein is not produced.
• This is epigenetic, and therefore in principle reversible. DNMT inhibitors (e.g. azacitidine, decitabine) demethylate CpG islands and can restore expression of silenced tumour suppressors. They are used clinically in myelodysplastic syndromes.
• Hypermethylation of MLH1 in colorectal cancers silences mismatch repair, producing microsatellite-instability tumours that respond to immune checkpoint inhibition — an example of how an epigenetic event in one gene produces a therapeutic target.

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The Hallmarks of Cancer

The hallmarks-of-cancer framework, proposed by Douglas Hanahan and Robert Weinberg in 2000 and revised in 2011, organises the diverse properties of cancer cells into a small set of acquired capabilities. (Their framework is paraphrased here — no verbatim quotation from Hanahan and Weinberg's papers is reproduced.)

The principal hallmarks include:

1. Sustained proliferative signalling — driven by oncogene activation (RAS, MYC, HER2).
2. Evasion of growth suppressors — driven by tumour suppressor loss (TP53, RB1, CDKN2A).
3. Resistance to cell death — apoptosis pathways are dampened (BCL2 over-expression; TP53 loss).
4. Replicative immortality — telomerase is reactivated, escaping replicative senescence.
5. Induction of angiogenesis — the tumour secretes VEGF and recruits a blood supply.
6. Activation of invasion and metastasis — cells lose adhesion (E-cadherin downregulation), invade adjacent tissue, intravasate, and seed distant sites.
7. Reprogramming of cellular metabolism — aerobic glycolysis (the Warburg effect).
8. Evasion of immune destruction — tumour cells acquire immune-checkpoint ligands (PD-L1) or HLA-loss variants.

Two enabling features underlie acquisition of these hallmarks: genome instability and mutation (which generates the variants on which selection acts) and tumour-promoting inflammation.

A typical tumour acquires these capabilities over many years and many cell divisions, in a stepwise sequence often involving driver mutations in 5–10 genes. Colorectal adenoma-to-carcinoma progression (with sequential APC → KRAS → TP53 mutations) is the classical example.

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Targeted Therapies

The traditional approach to cancer treatment — chemotherapy, radiotherapy — kills rapidly dividing cells indiscriminately and has substantial systemic toxicity. Targeted therapies exploit the specific molecular abnormalities of the tumour, sparing normal cells.

Trastuzumab (Herceptin) for HER2-positive breast cancer

• HER2 is a receptor tyrosine kinase that is over-expressed in ~15–20% of breast cancers (typically via gene amplification).
• Trastuzumab is a monoclonal antibody against the extracellular domain of HER2.
• Binding blocks HER2 signalling and recruits immune effector cells via antibody-dependent cellular cytotoxicity.
• Tumours are tested for HER2 status (immunohistochemistry, FISH for gene amplification) before treatment; only HER2-positive tumours respond.
• The drug has substantially altered outcomes for HER2-positive breast cancer, particularly in combination with chemotherapy. (Reviewers should consult contemporary clinical trial publications for current quantitative survival figures; the exact percentage improvement varies by subset and treatment regimen.)

Imatinib (Gleevec) for BCR-ABL-positive chronic myeloid leukaemia

• The Philadelphia chromosome — a translocation between chromosomes 9 and 22 — produces the BCR-ABL fusion gene, encoding a constitutively active tyrosine kinase that drives the chronic phase of CML.
• Imatinib is a small molecule that binds the ATP-binding site of BCR-ABL and inhibits its kinase activity.
• Imatinib transformed CML from a uniformly fatal disease into a chronic condition managed with daily oral medication. (Quantitative response and survival figures should be drawn from contemporary clinical trial reports; the magnitude of effect is substantial but the precise numbers shift with longer follow-up.)

Other examples

• EGFR inhibitors (gefitinib, erlotinib, osimertinib) in EGFR-mutant non-small-cell lung cancer.
• BRAF inhibitors (vemurafenib, dabrafenib) in BRAF V600E mutant melanoma.
• PARP inhibitors (olaparib) in BRCA1/2 mutant tumours — exploits the synthetic-lethal interaction between BRCA loss and PARP inhibition.

Exam Tip: Targeted therapies illustrate the practical payoff of understanding oncogene biology. The drug is matched to the specific molecular driver in each tumour — a principle of precision medicine or personalised oncology.

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Ethical Considerations

The genetic understanding of cancer raises several ethical questions:

• Predictive genetic testing. BRCA1/2 testing is offered to individuals with strong family histories of breast or ovarian cancer. A positive result indicates substantially elevated lifetime risk and prompts difficult decisions: enhanced surveillance, chemoprevention (tamoxifen), or risk-reducing surgery (prophylactic mastectomy / oophorectomy). The psychological burden of a positive result, and the implications for relatives who may or may not wish to know their own status, are non-trivial.
• Access to targeted therapies. Drugs such as trastuzumab and imatinib are extraordinarily expensive (typically tens of thousands of pounds per patient per year). NICE and equivalent bodies must decide whether each new drug represents acceptable cost-effectiveness; some patients in poorer countries lack access entirely. The benefits of precision medicine are not equally distributed.
• Insurance and employment discrimination. Knowledge of a BRCA mutation could in principle disadvantage carriers in insurance markets. In the UK, the Genetic Insurance Code restricts use of predictive genetic test results by insurers.

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Specimen Question 1 — 9 marks (modelled on the AQA paper format)

Question: Explain the difference between proto-oncogenes and tumour-suppressor genes, and discuss why mutations in these two classes of gene have different consequences for the cell.

Mark scheme decomposition by AO:

Mark	AO	Awarded for
1	AO1	Proto-oncogene normally promotes cell division (growth factor / receptor / signal kinase / TF)
2	AO1	Tumour-suppressor gene normally restrains cell division or drives apoptosis
3	AO2	Oncogene mutation is gain-of-function — hyperactive / constitutive protein
4	AO2	Tumour suppressor mutation is loss-of-function — protein non-functional or not made
5	AO2	Oncogenes are dominant at cellular level — one mutated allele sufficient
6	AO2	Tumour suppressors are recessive at cellular level — both alleles must be inactivated
7	AO1	Example oncogenes: RAS / MYC / HER2
8	AO1	Example tumour suppressors: TP53 / RB1 / BRCA1 / 2
9	AO3	Synthesis: net effect is acceleration of cell cycle (oncogenes) or removal of brake (TS) — both contribute to uncontrolled division

Grade C model answer (~170 words)

Proto-oncogenes are genes that help cells to divide. When they are mutated they become oncogenes which make the cell divide too much. Tumour-suppressor genes do the opposite — they stop the cell from dividing or cause it to die. When tumour-suppressor genes are mutated the cell can divide when it should not. So both kinds of mutation lead to cancer but they work in opposite ways. Oncogenes are gain-of-function so they make the protein work too much. Tumour-suppressor genes are loss-of-function so the protein stops working. An example of an oncogene is RAS. An example of a tumour-suppressor gene is p53. Tumour-suppressor genes usually need two mutations because if one allele still works the cell is fine. Oncogenes only need one mutation because one mutated allele is enough to make the cell divide too much. So oncogenes are dominant in the cell and tumour-suppressor genes are recessive.