Carcinogenesis: Causes, Molecular Stages, Risk Factors and Prevention

Carcinogenesis is the multistep transformation of a normal cell into a malignant clone. It usually requires accumulated genetic and epigenetic changes, selection of fitter subclones and interaction with the tissue microenvironment. Carcinogens can initiate DNA damage, promote expansion of an already altered clone or support progression toward invasion and metastasis.

Learning outcomes

By the end of this page, the learner should be able to explain the stages and molecular basis of carcinogenesis, classify carcinogens, distinguish genotoxic from non-genotoxic mechanisms, describe inherited susceptibility and tumour evolution, link important exposures to cancers, and apply prevention and emergency principles.

1. Definition and the multistep model

Carcinogenesis is not a single event. A cell acquires a heritable growth advantage, expands clonally and accumulates further changes. The classic model uses three overlapping conceptual stages:

Stage	Core event	Typical features
Initiation	Permanent alteration in DNA or stable gene regulation	Mutation, chromosomal rearrangement, viral integration or epigenetic reprogramming
Promotion	Selective expansion of initiated cells	Chronic inflammation, hormones, repeated injury or proliferative stimuli; may regress if the stimulus stops early
Progression	Additional changes produce aggressive subclones	High-grade atypia, invasion, angiogenesis, metastasis, immune escape and therapy resistance

The stages overlap and are not a mandatory sequence for every tumour. A single exposure can have more than one role, and inherited susceptibility may lower the number of additional steps required.

2. Genetic targets in carcinogenesis

2.1 Oncogenes

Proto-oncogenes normally promote controlled growth, survival or angiogenesis. Activation by mutation, amplification, translocation or excessive signalling converts them into oncogenes. Examples include RAS pathway activation, MYC amplification and growth-receptor overexpression.

2.2 Tumour-suppressor genes

Tumour suppressors restrain proliferation, repair damage or trigger cell death. Loss of TP53, RB, APC, PTEN or other suppressor pathways removes cellular brakes. Both alleles may need to be lost in a classic “two-hit” pattern, although haploinsufficiency and dominant-negative effects occur.

2.3 DNA-repair genes

Defects in mismatch repair, homologous recombination, nucleotide-excision repair or other pathways increase the mutation rate and genomic instability. A repair defect may be inherited or acquired in the tumour.

2.4 Apoptosis and senescence pathways

Cancer cells may resist apoptosis, inactivate checkpoints, reactivate telomerase or bypass senescence. They survive conditions that would remove normal damaged cells.

2.5 Non-coding and epigenetic regulation

Promoter methylation, histone modification, non-coding RNA and enhancer changes can silence suppressors or activate growth pathways without altering the protein-coding sequence.

3. Genotoxic and non-genotoxic carcinogens

Mechanism	How it acts	Examples
Direct genotoxic	Directly damages DNA or forms adducts	Ionising radiation, some alkylating chemicals
Metabolic activation	Procarcinogen is converted to a reactive metabolite	Polycyclic aromatic hydrocarbons and aflatoxin metabolites
Oxidative stress	Reactive oxygen species damage DNA, proteins and membranes	Chronic inflammation, smoke and some metals
Epigenetic	Alters methylation, chromatin or regulatory RNA	Some chemicals, viral proteins and chronic inflammation
Hormonal/proliferative	Stimulates cell division, increasing opportunities for replication errors	Oestrogenic, androgenic or other endocrine environments
Immunosuppressive	Reduces immune surveillance of altered cells	Transplant immunosuppression, advanced immunodeficiency

Carcinogenic hazard and individual risk are different. Hazard means an agent can cause cancer; risk depends on dose, route, duration, timing, susceptibility and co-exposures.

4. Physical carcinogens

Ultraviolet radiation

UVB can create pyrimidine dimers and other DNA lesions, especially in skin. Repeated sun exposure, tanning devices and childhood burns increase cumulative risk of basal-cell carcinoma, squamous-cell carcinoma and melanoma. Protection includes shade, clothing, sunscreen and avoiding artificial tanning.

Ionising radiation

X-rays, gamma rays and radioactive particles can create single- and double-strand breaks and chromosomal rearrangements. Risk increases with dose and is influenced by age and tissue. Use diagnostic imaging when clinically justified and apply radiation-safety principles.

Other physical factors

Chronic thermal injury, foreign-body inflammation and selected occupational exposures may contribute to malignant transformation. A persistent non-healing burn scar or ulcer requires assessment.

5. Chemical carcinogens

Exposure	Mechanism/associated risk	Prevention focus
Tobacco smoke	Multiple DNA adducts, oxidative stress, chronic inflammation; lung and many other cancers	Do not smoke; cessation and smoke-free environments
Alcohol	Acetaldehyde, oxidative stress and synergy with tobacco	Reduce or avoid; counsel at-risk patients
Aflatoxin contamination	Reactive metabolites can mutate tumour-suppressor pathways	Food storage, inspection and hepatitis prevention
Asbestos	Fibres cause chronic inflammation and mesothelial injury	Occupational control, protective equipment and surveillance
Benzene	Marrow toxicity and chromosomal injury	Industrial controls and exposure monitoring
Arsenic and some metals	Oxidative, epigenetic and DNA-repair effects	Safe water, occupational controls and regulation

Occupational history should include job tasks, duration, protective equipment, ventilation and co-workers with similar symptoms. Record suspected exposure accurately and refer through occupational-health services.

6. Biological carcinogens

Human papillomavirus (HPV)

High-risk HPV proteins interfere with p53 and RB pathways and can cause persistent epithelial dysplasia and cervical cancer. HPV is also linked to anal, penile, vulvar, vaginal and oropharyngeal cancers. Vaccination, safer-sex counselling and evidence-based cervical screening reduce risk.

Hepatitis B and C viruses

Chronic hepatic inflammation, regeneration, fibrosis and viral effects increase hepatocellular carcinoma risk. Hepatitis B vaccination and prevention of blood/sexual transmission are important; chronic infection requires testing and appropriate antiviral care.

Epstein–Barr virus

EBV contributes to selected lymphomas, nasopharyngeal carcinoma and other malignancies, particularly with immune dysregulation or specific cofactors. Most EBV infections do not cause cancer.

Helicobacter pylori

Chronic gastric inflammation and mucosal atrophy increase gastric adenocarcinoma and some lymphoid tumour risk. Diagnose and eradicate infection according to local guidance when indicated.

Other infection-related pathways

HIV-related immunosuppression increases risk of Kaposi sarcoma, lymphomas and infection-associated cancers. Parasites such as schistosomes and liver flukes are associated with selected urinary or biliary cancers in endemic settings.

7. Chronic inflammation and tissue injury

Persistent inflammation produces reactive oxygen species, cytokines, growth factors, angiogenesis and repeated cycles of cell death and regeneration. Examples include inflammatory bowel disease, chronic hepatitis, reflux injury, chronic pancreatitis, chronic wounds and long-standing osteomyelitis. Treating the underlying inflammation and monitoring high-risk patients can interrupt the promotion stage.

8. Inherited susceptibility

Inherited variants do not guarantee cancer; they lower the threshold for acquiring additional somatic changes. Examples include BRCA1/2-associated breast/ovarian/prostate/pancreatic cancer risk, APC-associated polyposis, mismatch-repair syndromes and TP53-associated cancer predisposition. Clues include young age at diagnosis, multiple primary cancers, bilateral disease, a characteristic tumour spectrum and several affected close relatives.

Use genetic counselling before predictive or family testing. A tumour mutation is not automatically a germline mutation; inherited risk requires appropriate testing in non-tumour tissue.

9. Field cancerisation and clonal evolution

Field cancerisation

Long-term exposure can create a broad field of altered epithelial cells, especially in the aerodigestive tract. A patient may develop multiple primary tumours or local recurrences even after one lesion is removed.

Clonal evolution

Mutations and epigenetic changes create subclones. The microenvironment and treatment select cells that proliferate faster, invade or resist therapy. This explains heterogeneity between primary and metastatic lesions and why a cancer can recur years later.

10. Angiogenesis, invasion and metastasis during progression

• Angiogenic switch: the tumour produces pro-angiogenic factors and recruits abnormal vessels.
• Local invasion: loss of adhesion and extracellular-matrix degradation allow cells to cross tissue boundaries.
• Intravasation/extravasation: cells enter and leave blood or lymphatic vessels.
• Colonisation: only a minority of disseminated cells adapt to a distant organ’s microenvironment.
• Immune escape: successful clones suppress or avoid immune attack.

11. Prevention and early detection

Primary prevention

• Stop tobacco use and reduce second-hand smoke.
• Limit alcohol, maintain healthy activity and weight, and reduce processed exposures where possible.
• Vaccinate against HPV and hepatitis B according to national programmes.
• Protect skin from excessive UV; use occupational controls for asbestos, benzene and other hazards.
• Use safe food storage and clean water to reduce infection-related and toxin-related risk.

Secondary prevention

• Participate in guideline-based cervical, breast, colorectal and other locally recommended screening.
• Investigate persistent symptoms rather than repeatedly treating them empirically.
• Surveil patients with inherited syndromes, chronic inflammation or known premalignant lesions.

Tertiary prevention

After diagnosis, prevent recurrence and complications with appropriate treatment, rehabilitation, surveillance and supportive care. A cancer diagnosis should trigger smoking cessation and vaccination review, not therapeutic nihilism.

12. Emergency relevance

13. Case applications

Case 1: Persistent cervical abnormality

A patient has repeated abnormal cervical screening and high-risk HPV. This is not yet invasive cancer, but persistent infection and dysplasia represent a progression pathway. Ensure colposcopy or local follow-up rather than waiting for symptoms.

Case 2: Chronic hepatitis and liver mass

A patient with long-standing hepatitis develops weight loss and right-upper-quadrant pain. Assess liver function, imaging and tumour markers within the appropriate pathway, while also evaluating acute bleeding, infection or decompensation.

Case 3: Occupational dust exposure and haemoptysis

A worker with a long exposure history presents with haemoptysis and weight loss. Stabilise airway and circulation, assess bleeding and infection, obtain imaging and arrange tissue diagnosis and occupational documentation.

14. Exam pearls

• Initiation is permanent; promotion expands initiated cells; progression produces aggressive subclones.
• Carcinogenesis is usually multistep, clonal and shaped by selection.
• Genotoxic agents damage DNA; non-genotoxic agents may promote proliferation, inflammation, hormonal signalling or immune escape.
• Inherited susceptibility is not the same as inherited cancer itself.
• HPV, hepatitis viruses, H. pylori, tobacco, alcohol, UV and ionising radiation are important preventable or controllable causes.
• Prevention and early detection reduce cancer burden even when not every case is avoidable.

References and further reading

• NCI: The genetics of cancer.
• NCI: Initiation, promotion and progression in carcinogenesis.
• WHO: Preventing cancer.
• IARC: Mechanisms of carcinogenesis.
• Use local oncology, occupational-health, immunisation, HIV/hepatitis and cancer-screening protocols.