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Purpose and principlesIndications, selection and cautionsMethod and interpretationClinical next stepsRisks, monitoring and follow-upSpecial situationsCommon pitfallsQuestionsSources
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Educational draft · awaiting clinical reviewThe full textbook explains uncertainty but does not replace live national or local guidance, specialist advice, or current prescribing information.

Cancer genetics, oncogenes and tumour suppressor genes

Oncology and palliative care · UK scope · Sources checked 27 Aug 2026 · Clinical review pending

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Purpose and principles

Explain how acquired and inherited genomic alterations drive malignant behaviour, distinguish driver from passenger findings, and interpret tumour and germline results without overstating certainty.

Normal tissues balance proliferative signals against growth inhibition, DNA repair, differentiation, senescence and apoptosis. Malignant clones acquire combinations of changes that disturb these systems. Proto-oncogenes become oncogenes through activating sequence variants, amplification or rearrangement; tumour-suppressor function is lost through variants, deletion or epigenetic silencing. Genomic instability then increases diversity within the tumour, allowing treatment-resistant subclones to emerge under selection pressure.

Genomic testing serves several different questions. Diagnostic markers help classify a tumour; prognostic markers estimate natural history; predictive markers indicate the chance of response or toxicity from a treatment; inherited testing estimates constitutional cancer susceptibility. These purposes must be labelled separately. A molecular report is interpreted with morphology, immunohistochemistry, tumour site, stage, prior therapy and assay validation rather than used as a stand-alone answer.

The safe sequence is to define the clinical question, choose tumour or germline material appropriately, confirm adequate cellularity, review the laboratory's report and limitations, and discuss actionable findings in the relevant multidisciplinary team. Potential germline implications from tumour testing should prompt a governed genetics pathway rather than direct testing of relatives from an unconfirmed result.

Key points

  • Cancer develops through accumulated alterations that confer selective growth, survival, invasion or immune-evasion advantages; no single universal mutation explains every tumour.
  • Oncogenes usually act through gain of function, so one activated allele can promote signalling; examples include RAS pathway activation and ERBB2 amplification.
  • Tumour-suppressor genes restrain proliferation, repair DNA or trigger cell death; loss of both functional copies commonly removes that restraint, although mechanisms vary.
  • DNA-repair defects increase the rate at which other alterations accumulate and may create treatment biomarkers such as mismatch-repair deficiency or homologous-recombination deficiency.
  • Tumour-only testing cannot establish constitutional status; a finding that may be inherited needs consented confirmatory testing in non-tumour tissue through a governed genetics pathway.
  • Variant allele fraction, sample purity, copy number and technical limits influence interpretation; a negative panel does not exclude cancer or inherited susceptibility.
  • Actionability is context-specific: the same molecular alteration may predict benefit in one tumour type but have uncertain value in another.
  • Germline findings require consent, genetics expertise and a plan for relatives, insurance questions, reproductive implications and data governance.

Indications, selection and cautions

Oncogene activation

A hotspot activating variant, fusion or amplification can create continuous proliferative signalling and sometimes a targetable dependency.

Tumour-suppressor loss

Biallelic functional loss removes a brake on cell cycling, DNA-damage response or apoptosis; loss may involve sequence change, deletion or methylation.

Repair-deficient phenotype

Mismatch-repair protein loss, microsatellite instability or a homologous-recombination signature indicates altered repair biology but requires tumour-specific interpretation.

Possible germline signal

Young age, multiple primaries, characteristic tumour type, bilateral disease or a pathogenic variant at a plausible allele fraction can justify genetics referral.

Resistance evolution

A previously responsive cancer may acquire secondary target alteration, pathway bypass or resistant clonal selection, requiring repeat tissue or circulating-DNA discussion.

Method and interpretation

  1. 01
    Histology and immunohistochemistryFirst step
    Why
    Establish lineage and direct focused molecular testing.
    Interpretation and limitations
    Morphology remains the diagnostic anchor; immunophenotype narrows origin and can demonstrate protein loss, but staining artefact and internal controls matter.
  2. 02
    Validated somatic sequencing panel
    Why
    Identify diagnostic, prognostic or predictive tumour alterations.
    Interpretation and limitations
    Interpret pathogenicity, allele fraction, coverage, tumour purity and approved indication together; variants of uncertain significance are not treatment instructions.
  3. 03
    Copy-number and fusion testing
    Why
    Detect amplifications, deletions and rearrangements missed by small-variant assays.
    Interpretation and limitations
    The appropriate method depends on the suspected event; an assay that cannot detect a fusion cannot exclude it.
  4. 04
    Germline genetic testing
    Why
    Confirm inherited predisposition when personal, family or tumour evidence meets criteria.
    Interpretation and limitations
    Use consented blood or another non-tumour sample through clinical genetics; classification and family action follow current laboratory and national genomic pathways.
  5. 05

Clinical next steps

01DefineFrame the molecular questionFirst stepA cancer diagnosis may need classification, inherited-risk assessment or a treatment biomarker.+
  1. 1Confirm histological diagnosis, tumour site, stage, available material and the precise decision that a molecular result would change.
  2. 2Choose an assay whose validated scope covers the required variant types, and record whether testing is somatic, germline or paired.
  3. 3Obtain appropriate consent, including possible inherited implications and the limits of a negative or uncertain result.
02InterpretIntegrate the laboratory resultA molecular report identifies a pathogenic, uncertain or absent alteration.+
  1. 1Review specimen quality, analytical limitations, variant classification and tumour cellularity before accepting biological absence.
  2. 2Separate diagnostic, prognostic and predictive meaning, then confirm whether actionability is licensed or recommended for this tumour context.

Risks, monitoring and follow-up

  • Record specimen source, tumour content, assay version, detectable variant classes and report date so later clinicians understand what a negative result did and did not test.
  • Revisit genomic interpretation when classification databases, licensed indications or disease context changes; variant meaning is not permanently fixed.
  • Track response and resistance using clinical assessment and standard imaging, adding repeat molecular testing only when it can change a realistic treatment decision.
  • For inherited syndromes, maintain a family-aware surveillance record, document which relatives were offered genetics contact and preserve confidentiality boundaries.
  • Report unexpected assay discordance, sample failure or suspected germline significance to pathology or genetics rather than improvising an explanation.

Special situations

Driver does not mean target

A biologically important driver may have no effective medicine, while some treatment biomarkers reflect pathway state rather than the initiating mutation.

Two-hit is a model

Many tumour-suppressor genes follow biallelic loss, but dominant-negative effects, haploinsufficiency and epigenetic mechanisms make the biology more varied.

Tumours are heterogeneous

One block samples only part of a cancer; spatial and temporal heterogeneity can explain discordant biopsies and later resistance.

Uncertain means non-actionable

A variant of uncertain significance should not trigger targeted treatment, prophylactic surgery or predictive testing of relatives.

Negative is assay-bounded

No detected alteration means none within the sample and method's reliable range, not proof that the cancer lacks genomic drivers.

Common pitfalls

  1. 01

    Calling every detected variant a cancer driver.

  2. 02

    Treating tumour-only sequencing as proof of inheritance.

  3. 03

    Ignoring copy-number, fusion and sample-purity limitations.

  4. 04

    Using a biomarker outside its validated tumour context.

  5. 05

    Acting clinically on a variant of uncertain significance.

  6. 06

    Forgetting consent and family consequences before germline testing.

Practice

Two practice questions

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Question 1 of 2
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Oncology and palliative careOriginal SBA

Tumour-only result

A colorectal tumour panel reports a pathogenic mismatch-repair gene variant at a substantial allele fraction, but no constitutional sample has been tested. What is the correct interpretation?

Choose one answer, then submit
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Sources and review status4 sources · checked 27 Aug 2026 · clinical review pending+
Sources

Sources and review status

National guidance is shown before implementation-dependent detail. Apply principles in context and verify current guidance when a decision affects care. Source check completed 27 Aug 2026; clinical approval remains outstanding.

  • Genomics Education: constitutional versus somatic variantsWhy tumour-only findings do not establish inheritance and when confirmatory constitutional testing is required.
  • Royal College of Pathologists cancer datasetsIntegrated morphology, biomarker reporting and specimen-quality standards for cancer pathology.
  • NHS England National Genomic Test DirectoriesCurrent national eligibility and test scope for validated genomic investigations in NHS care.
  • NHS England cancer programmeMultidisciplinary cancer pathways and national service context for molecularly informed treatment.

Editorial contact: Doctor’s Passport editorial team. Source-check date is separate from clinical approval. Report a content problem · Content changes

Authoring stateComplete draftClinical stateAwaiting reviewJurisdictionUnited Kingdom
Repeat biopsy or circulating tumour DNA
Why
Investigate resistance or obtain material when archival tissue is inadequate.
Interpretation and limitations
Liquid biopsy may reveal circulating alterations but false negatives occur with low shedding; tissue remains necessary when histological transformation is possible.
  • 3Discuss discordant or complex findings with molecular pathology and the tumour multidisciplinary team before changing treatment.
    • 03InheritManage possible constitutional riskTumour findings or the clinical history suggest a germline predisposition.+
    1. 1Refer through clinical genetics or the relevant national genomic test directory pathway rather than labelling a tumour result hereditary.
    2. 2Confirm the variant in a non-tumour sample with informed consent and explain uncertain, secondary and family implications.
    3. 3If pathogenic, create syndrome-specific surveillance and cascade-testing plans; if uninformative, continue risk assessment from the phenotype and pedigree.