L15- Origins of cancer and early detection recap

what are the origins of cancer

changes in cell phenotype

• loss of function, de-differentiation, ability to metastasise and invade

how do constitutional and somatic genomics determine cancer risk

errors/mutations are inevitable

how is cancer a multistep process driven by the acquisition of somatic mutations

• spontaneous DNA replication errors

• endogenous DNA damage (molecular oxygen)

• exogenous DNA damage (UV, ionising radiation, BPDE)

→

• DNA damage caused DNA mutation (in TS genes and proto-oncogenes)

→ (genetic instability/antiapoptotic)

cancer

What are high penetrance constitutional genetic variants in cancer?

• Rare inherited (monogenic) mutations that greatly increase lifetime cancer risk

• eg hereditary breast/ovarian cancer (e.g. BRCA genes)

  • One defective allele is inherited

  • Second allele becomes mutated/silenced (somatic “second hit”)

• Only a small proportion of cancers are due to these mutations

What is the difference between monogenic and polygenic cancer susceptibility?

• Monogenic (single gene):

  • Rare in the population

  • High penetrance → strong effect on disease risk

• Polygenic (multiple genes):

  • Common in the population

  • Low penetrance → each gene has a small effect

• Most people have polygenic risk, where many low-risk alleles combine

• Cancer risk increases gradually with accumulation of multiple low-penetrance variants

give an example of a polygenic disease

chronic lymphocyte leukaemia (CLL)

>45 loci carrying common variants accounting for 25% of the heritable risk of CLL

How do constitutional (inherited) and somatic mutations contribute to cancer over time?

• Constitutional variants (inherited):

  • Stronger influence early in life

  • Declining relative contribution over time

  • Studied in aetiological studies (causes of cancer)

• Somatic mutations (acquired):

  • Accumulate over time

  • Increasing contribution as disease progresses

  • More important around diagnosis and treatment

  • Studied in prognostication studies (outcomes, progression)

How does tolerance of genetic variation differ between constitutional and somatic genomes?

• Constitutional genome:

  • Less tolerant of genetic variation

  • Large changes → syndromes (e.g. trisomy 13, 18, 21)

• Somatic genome:

  • More tolerant of genetic variation

  • Can have large changes (e.g. hyperdiploidy in AML)

• Many somatic mutations have large functional effects that are not tolerated in the constitutional genome

is cancer always an age associated disease

no

• eg acute lymphoblastic leukaemia in children

but it is still driven by acquisition and is still affected by exposures

how many somatic mutations are needed for cancer

to 10 driver mutations are needed to cause cancer!

• occur in established cancer genes (TP53, MYC)

• Major cancer genes are known but many are yet to be identified

• Most mutations observed in cancer cells are non-functional passenger mutations (genetic instability)

• Identifying driver mutations from passenger mutations is not always easy

give examples of cancers and how many mutations they usually require

• 1 mutation can cause cancer in some settings (ie. some leukaemias)

• Liver cancer requires an average of 4 mutations

• Colorectal cancer requires up to 10 mutations

in what ways is cancer a multistep process

genetically

epigenetically

transcriptionally

phenotypically

What does this AML example show about mutation accumulation over time?

• AML evolves through multiple genetic “hits” (mutations)

• At presentation: ~3 key mutations (e.g. TET2 + NPM1)

• At relapse: additional mutation acquired (e.g. FLT3)

• Shows clonal evolution: cancer changes and becomes more complex over time

• Relapse often involves new mutations → disease progression / treatment resistance

What is the role of TET2 and its global effect on cells?

• TET2 regulates DNA methylation (epigenetic control)

• Converts methylated cytosine → hydroxymethylcytosine (demethylation pathway)

• Methylation → transcriptional repression

• Single mutation effect:
  Genome → Epigenome → Transcriptome → Proteome

• Leads to global changes in gene expression

• Results in altered cell phenotype:

  • Loss of function

  • De-differentiation

  • Increased invasion/metastasis

What are the stages of cancer development (malignant transformation)?

• Cancer develops as a multi-step process:
  Normal → Hyperplasia → Dysplasia → Cancer (neoplasia)

• Hyperplasia: ↑ cell number

• Dysplasia: abnormal cell phenotype (pre-cancer)

• Cancer: uncontrolled abnormal cell growth

• Driven by accumulation of driver gene mutations

• Overall process = malignant transformation

What are key definitions and concepts in neoplasia (cancer)?

• Neoplasia = cancer

• Benign: cannot invade other tissues

• Malignant: can invade other tissues

• These terms mainly apply to solid tumours (not myeloid or B-cell cancers)

• Haematopoietic cancers:

  • Derived from non-adherent cells

  • Disseminate via blood and lymphatic systems

• “Acute” vs “chronic” → describes disease aggressiveness

how common is pre cancer

very common

• we all have pre cancer as we all have cancer drien somatic mutations

Example: Clonal haematopoiesis - clonal expansion of cells in the blood and bone marrow with leukaemia-initiating mutations.

is clonal haematopoiesis dangerous in all individuals

no- its healthy in asymptomatic individuals

What is clonal haematopoiesis and how does it relate to cancer risk?

• Clonal haematopoiesis: presence of blood cell clones with somatic mutations

• Associated with increased risk of haematological cancers (especially AML)

• Individuals with clonal haematopoiesis have:

  • Higher cumulative incidence of cancer over time

  • Significantly greater risk (p < 0.001)

• Individuals without mutations have much lower risk

• Key idea: early mutations in blood cells can predispose to later cancer development

What is essential thrombocythaemia and what are its key features?

• A pre-leukaemic blood disorder where the body makes too many platelets

• Commonly involves mutations (especially JAK2, among others like DNMT3A, TET2, ASXL1)

• Causes abnormal platelet function → risk of clotting or bleeding

• Has a low risk of progression to acute myeloid leukaemia (AML) (~0.1–0.2% per year)

• Considered close to AML in disease spectrum (“one mutation away”)

when is a cell a cancer cell

how is cancer screened

is there a clinical benefit to an early cancer diagnosis

yes for most cases- certainly for many solid cancers

in which cancer is early detection urgently needed

Pancreatic cancer

In cancer screening, what are false positives and false negatives, and why do they matter?

• False positive: Test says cancer is present when it isn’t → causes unnecessary anxiety, further tests, and cost

• False negative: Test misses cancer when it is present → delays diagnosis and treatment

• Even with good tests, both can occur (e.g., 99 false positives vs 1 false negative in this example)

• A perfect test would have zero false positives and false negatives

• Screening decisions must balance accuracy, cost, and practicality

what needs to be considered for tests for cancer diagnosis

Tests for ALL cancers?

Tests for specific cancers?

Cost

Logistics

(easy to perform? painful?)

how can dogs be used in cancer testing

Detects volatile organic compounds (VOCs) generated by cancer cells and exhaled excreted via the lungs in the breath.

Primarily aimed at cancers of the gut (oesophagus, stomach, colon pancreas – plus liver)

what is the prostate specific test

Prostate specific antigen (PSA)

Blood test, painless, cheap!

What does PSA measure and what limits its usefulness as a prostate cancer test?

• PSA reflects prostate tissue activity, not cancer specifically

• Levels increase with age, even in healthy men

• Raised PSA can be due to benign prostatic hyperplasia (BPH), infection, or inflammation

• Therefore, PSA is not specific for cancer → risk of false positives

• Definitive diagnosis requires biopsy, which is invasive, costly, and carries risks

what is PSA

Prostate specific antigen (PSA) – a molecule expressed by prostate cells (normal and cancerous) detectable in the bloodstream

How does PSA level at age 60 relate to future prostate cancer risk?

• Higher PSA at age 60 → higher lifetime risk of prostate cancer, metastasis, and death

• Risk increases in a stepwise fashion across PSA percentiles

• Even moderately raised PSA significantly increases long-term risk

• However, PSA testing still has high false positive and false negative rates

• Therefore, PSA is useful for risk stratification, but not a perfect diagnostic test

do all people with prostate cancer die from it/have the same prognosis?

no, the outcome of prostate cancer patients very heterogeneous

Only 10-15% of prostate cancers are aggressive (fast growing, more likely to spread)

85-90% are indolent (slow growing, less likely to spread)

• most men die with prostate cancer than because of it

what is needed to account for prostate cancer outcomes being very heterogeneous

We need better diagnostic markers for differentiating between aggressive cancers that kill patients and those that are less aggressive and are not life limiting

Test results also need to indicate a clear clinical intervention (ie. help doctors and patients to make decisions on the way forward)

what is the natural history of chronic lymphocytic leukaemia (CLL)

clinical course of disease is very heterogeneous

1. monoclonal B cell lymphocytosis (asymptomatic)

2. CLL diagnosis (asymptomatic or weakly symptomatic)

3. treatment (heavily symptomatic)

describe the outcome of patients with CLL

Most patients are diagnosed with early stage A disease and many will never require treatment (dying with CLL, not because of it) but approximately 40% will progress to requiring treatment.

Clinical strategy for stage A patients is currently “watch-and-wait”

is there a benefit to treating CLL early

Ibrutinib - Bruton’s tyrosine kinase inhibitor

Need to accurately identify those patients who will develop symptomatic disease and need treatment.

Don’t want to treat patients who will never progress

What are key prognostic markers in CLL and what do they indicate?

• IGHV mutation status (genetic marker):

  • Mutated → better prognosis (longer survival)

  • Unmutated → worse prognosis

• CD38 expression (phenotypic marker):

  • Negative → better prognosis

  • Positive → worse prognosis

• These markers help predict disease course and survival

• Ongoing question: can adding constitutional (inherited) genetic markers further improve prognostic models?

What is the aim of prognostic genome-wide association studies (GWAS) in CLL?

• Analyse millions of genetic variants across patients to find risk-associated loci

• Link inherited (constitutional) genetics with disease progression risk

• Identify patients at high risk of needing earlier treatment (shorter TTFT)

• Large datasets (e.g., UK CLL cohort) improve reliability of findings

• Goal: enhance prognostic models beyond existing markers

What is the significance of chromosome 6 and 10 markers in CLL progression?

• Specific genetic variants on chr6 (rs736456) and chr10 (rs3778076) are linked to CLL progression

• These variants are associated with shorter survival / earlier need for treatment (worse prognosis)

• Effect size is moderate (hazard ratios ~1.8–2)

• Findings are consistent across multiple cohorts (meta-analysis)

• Supports use of inherited genetic markers to improve prognostic prediction

What does the multivariate model show about predictors of CLL progression (TTFT)?

• Strong predictors of faster progression:

  • Unmutated IGHV (worst prognosis)

  • CD38 positive

  • chr6 and chr10 genetic variants

• ZAP-70 shows weaker/borderline significance

• Age and sex have little to no impact

• Combining clinical + somatic + inherited genetic markers improves prediction of time to first treatment