Core idea Disease begins when a genetic change alters a cellular function. In cancer, successive somatic and sometimes germline changes disable growth control, evade cell death, sustain replication, remodel tissue and enable invasion. The task for a doctor is to connect variant → molecular mechanism → cellular phenotype → clinical behaviour → treatment or prevention.
Learning outcomes
Distinguish germline from somatic disease variants; explain loss-of-function, gain-of-function, dominant-negative and haploinsufficient mechanisms; describe oncogenes, tumour-suppressor genes, apoptosis and DNA-repair pathways; recognise inherited cancer syndromes; and interpret molecular results for diagnosis, prognosis, targeted therapy and family counselling.
1. From variant to disease phenotype
A variant can alter a protein’s quantity, structure, location, interaction or regulation. A missense substitution may change an active site; a nonsense variant can truncate a protein; a splice-site variant can remove an exon; a copy-number change alters dosage; and a regulatory variant can change when a gene is expressed. The same gene may cause different phenotypes depending on the allele, tissue, developmental stage and modifying factors.
Not every variant causes disease. Interpretation combines population frequency, segregation, functional evidence, computational prediction, phenotype fit and previous clinical knowledge. A variant of uncertain significance should not be used alone for irreversible treatment or predictive testing.
2. Germline and somatic variation
| Feature | Germline variant | Somatic variant |
|---|---|---|
| Where present | Egg or sperm lineage and usually every cell. | Acquired in a cell or clone during life; may be absent from blood. |
| Inheritance | May pass to children. | Usually not inherited by children, though mosaic germline involvement is possible. |
| Clinical implication | Predisposition, inherited syndrome, congenital disease or pharmacogenetic effect. | Tumour initiation, progression, treatment resistance or acquired disease. |
| Testing | Blood or saliva often represents the constitutional genome. | Tumour tissue, circulating DNA or paired tumour-normal testing may be required. |
A germline predisposition is not the same as inevitable disease. Penetrance describes the proportion of people with a variant who develop the phenotype; expressivity describes the range of severity or features. A person may carry a high-risk allele and remain unaffected, while another develops cancer early.
3. Functional classes of disease variants
Loss of function
The gene product is absent or reduced. Recessive disease may require loss of both alleles, while haploinsufficiency occurs when one normal copy cannot provide enough product.
Gain of function
The altered protein is overactive, active in the wrong place or given a new activity. One allele may be sufficient, as in many oncogene activations.
Dominant-negative
The abnormal product interferes with the normal product, especially in multimeric proteins. The phenotype can be more severe than simple loss of one copy.
Dosage or regulatory change
Deletion, duplication, enhancer disruption or epigenetic silencing changes how much, where or when a gene is expressed.
4. Cancer as an evolutionary genetic disease
Cancer is usually monoclonal at origin but becomes genetically heterogeneous. A founding cell acquires a growth advantage and expands; additional mutations create subclones that differ in proliferation, invasion, immune evasion and treatment sensitivity. Selection by hypoxia, immunity or therapy can favour resistant clones.
Carcinogenesis is multistep. DNA damage, replication error, defective repair and epigenetic change accumulate over time. Chromosomal gains, losses, translocations, amplifications and deletions can alter many genes at once. Environmental exposures such as tobacco smoke, ultraviolet radiation, chronic inflammation and selected infections increase damage, but the clinical cancer reflects interaction between exposure, tissue context and host biology.
5. Four major gene groups in cancer
Proto-oncogenes and oncogenes — the accelerator
Proto-oncogenes normally promote appropriate growth and survival. Activating mutation, gene amplification, increased transcription or chromosomal translocation can convert them into oncogenes. Oncogene activation is generally a gain-of-function process; one altered allele can drive signalling. Examples include KRAS, MYC, ERBB2/HER2 and BCR::ABL1.
Tumour-suppressor genes — the brake
Tumour suppressors restrain cell-cycle entry, repair damage, maintain tissue architecture or trigger apoptosis. Their loss often follows the two-hit model: an inherited or early first hit reduces reserve, then a somatic second hit removes the remaining function. RB1, TP53, APC and PTEN illustrate different tumour-suppressor pathways.
DNA-repair genes — genome maintenance
Repair genes correct mismatches, double-strand breaks, crosslinks and ultraviolet damage. When repair is defective, mutation burden and chromosomal instability rise. BRCA1/2 deficiency impairs homologous recombination; mismatch-repair deficiency produces microsatellite instability and may cause Lynch syndrome.
Apoptosis and senescence regulators
Damaged cells should stop dividing, enter senescence or undergo programmed cell death. Altered p53 signalling, BCL-2 family balance, death receptors or telomere control allows abnormal cells to survive and continue dividing.
6. Key pathways and examples
TP53 responds to DNA damage and other cellular stress by inducing cell-cycle arrest, repair or apoptosis. Loss of p53 permits replication of damaged DNA and is common across cancers. Germline TP53 predisposition causes Li-Fraumeni syndrome and a broad spectrum of early malignancies.
RB–E2F control restrains the G1-to-S transition. Cyclin D–CDK activity phosphorylates RB, releasing E2F to activate DNA-synthesis genes. Disruption of RB, cyclins, CDKs or upstream signals removes this checkpoint.
APC–WNT signalling normally regulates beta-catenin degradation. APC loss allows beta-catenin accumulation and transcription of proliferative genes, contributing to familial adenomatous polyposis and colorectal cancer.
RAS–RAF–MEK–ERK transmits growth-factor signals. Activating RAS or pathway mutations can make the pathway constitutively active, so downstream growth continues without normal external stimulation.
PI3K–AKT–mTOR integrates growth and nutrient signals. Hyperactivation supports survival, metabolism and protein synthesis and can contribute to resistance.
Telomerase maintains telomeres in many cancers, allowing cells to escape the replicative limit that constrains most normal somatic cells.
7. Inherited cancer-predisposition syndromes
| Syndrome or gene | Characteristic pattern | Clinical reasoning |
|---|---|---|
| BRCA1/BRCA2 | Breast, ovarian, prostate and pancreatic cancer risk. | Risk assessment guides surveillance, reproductive counselling and selected targeted therapy. |
| Lynch syndrome: MLH1, MSH2, MSH6, PMS2, EPCAM | Colorectal, endometrial and other mismatch-repair-associated cancers, often at younger ages. | Tumour testing for mismatch repair or microsatellite instability can guide germline evaluation. |
| APC familial adenomatous polyposis | Numerous colorectal adenomas and high colorectal-cancer risk. | Early specialist surveillance and family testing are essential. |
| RB1 hereditary retinoblastoma | Early retinoblastoma and second-tumour risk. | Urgent ophthalmic and genetic evaluation; relatives may need assessment. |
| TP53 Li-Fraumeni syndrome | Multiple early cancers, including sarcoma, breast, brain and adrenal tumours. | Surveillance and radiation decisions require specialist genetics input. |
8. Recognising a hereditary cancer pattern
Red flags include several close relatives with the same or related cancers, unusually young diagnosis, bilateral or multifocal tumours, multiple primary cancers in one person, rare cancers, male breast cancer, ovarian or pancreatic cancer in a family, and ancestry associated with a founder variant. A small family does not exclude inherited risk because of few relatives, early deaths, adoption or incomplete information.
Construct a three-generation pedigree and record tumour type, pathology, age at diagnosis, bilateral disease, ancestry and whether relatives are affected on the maternal or paternal side. Test an affected relative first when possible because a negative result in an unaffected person may be uninformative.
9. Tumour testing and clinical interpretation
Pathology, immunohistochemistry, FISH, PCR, next-generation sequencing, copy-number analysis and liquid biopsy each answer different questions. Tumour sequencing may identify a targetable somatic alteration, but it can also reveal a possible germline finding that requires confirmation in a constitutional sample and genetic counselling.
A positive result may be actionable, prognostic, diagnostic or simply informative. A negative result means no alteration was detected by that assay; it does not prove the pathway is normal. A VUS should not guide major treatment or family testing. Always review specimen quality, tumour fraction, assay coverage and variant classification.
10. From genetic result to treatment
Precision oncology links a molecular alteration to a treatment or trial, but a biomarker is not a promise of response. Resistance may arise through a second mutation, pathway bypass, altered drug transport, clonal selection or inadequate drug exposure. Doctors must integrate molecular findings with stage, histology, performance status, organ function, patient preference and access.
Clinical questions before acting on a molecular report
- Is the variant germline, somatic or unresolved?
- Is it pathogenic and biologically relevant to this tumour?
- Is the test validated for this specimen and indication?
- Does an approved therapy or trial exist, and what is the evidence level?
- Could the result affect relatives or require genetic counselling?
- What surveillance is needed if the finding indicates inherited risk?
11. Prevention, surveillance and family implications
For germline predisposition, management may include earlier or more frequent screening, risk-reducing medication or surgery, lifestyle counselling, reproductive options and cascade testing. Recommendations must be syndrome-specific and updated as evidence changes. Do not offer a generic “cancer screen” without naming the organ, age, interval and responsible service.
12. Genetic counselling in cancer
Begin with the patient’s understanding and goals. Explain that a positive hereditary result may clarify risk for the patient and relatives but can also cause anxiety, affect family relationships and raise privacy concerns. Discuss testing benefits, limitations, possible results, insurance or discrimination concerns where applicable, and who will receive the report. Use non-directive communication and offer psychological support.
13. Examination summary
Cancer is a genetic disease of somatic cells, sometimes enabled by an inherited predisposition. Oncogenes are activated accelerators; tumour suppressors and DNA-repair genes are lost brakes and maintenance systems; apoptosis and telomere pathways determine survival. Multistep clonal evolution creates heterogeneity and resistance. Germline testing has implications for relatives, while tumour testing informs diagnosis, prognosis and targeted treatment but must be interpreted in clinical context.
