Lectures 7&8 - Cancer evolution Flashcards
Whats the difference between a benign tumour and a malignant tumour
Benign tumour:
Mutant clone of a cell
Localised growth
Normal function
Expands but expands within a capsule
Melignant tumour :
Multiple mutations
Disorganised growth
Loss of function
Intensive angiogenesis
Ulceration of the skin (in skin ancer)
What are possible reasons for a higher rate of cancer in humans than other species?
– Long post-reproductive lifespan if we didn’t have technology in society that allowed longer lifespan, genes wouldn’t be able to survive that are cancerous
– Mis-matched to risk factors generated by civilization (tobacco, alcohol, high-calorie, high-fat diets, pollution etc…)
– Highly invasive placentas produced by stem cells preadapted to metastasis
-Many polymorphisms are there to give you a slight advantage, but they modulate all forms of processes in body, but these advantages/polymorphisms can cause cancer in some cases
-Mutations in stem cells are more likely to cause cancer
Explain the Somatic mutation theory (SMT) of cancer
- Cancer begins with a genetic change in a single cell that passes it on to its progeny, thereby generating a clone of cells
- Cells within this population acquire further mutations so that eventually a sub-clone emerges that is able to grow or metastasize sufficiency to cause the death of the host
- SMT also explains the inherited susceptibility to cancers– Knudson’s ‘two-hit’ hypothesis (TSGs, Retinoblastoma)
What is micro-evolution
Change in the genetic composition that occurs over time in a population – e.g. Antibiotic resistance
What is macro-evolution
Major evolutionary change at or above the level of the species
–e.g. Speciation, generating a new species
What is somatic evolution?
- Accumulation of (epi)mutations in somatic cells of your body during your lifetime
– Not germ and stem cells
- These mutation occur in normal tissues and increase with age/ risk exposures
- They may affect the fitness of those cells and lead to positive selection of mutant clones
Define a Clone
Set of cells that all descend from a common ancestor cell. A clone is usually distinguished through inheritance of a distinctive genetic lesion (mutation) that occurred in the ancestor cell.
Define Neoplastic progression
the somatic evolutionary process by which normal tissue changes into malignant (cancerous) tissue
What does the The Shannon diversity index tell you
How diverse the species in a given community are
explain how clonal diversity measurements may have utility towards personalised cancer evolution forecasts
Number and how different clones are directly correlate with individual risk of having cancer
What is a driver mutation
Mutation that gives a selective advantage to a clone in its microenvironment, through either increasing its survival or reproduction. Driver mutations tend to cause clonal expansions
What is a passenger mutation
Mutation that has no effect on the fitness of a clone but may be associated with a clonal expansion because it occurs in the same genome with a driver mutation. This is known as a hitchhiker in evolutionary biology
What mechanisms generate diversity
Numerical chromosomal instability – a trisomy of chromosome 12 occurs in some fetal dissorders and cancer, seems to be selected for in B cell melignancies
Structural chromosomal instability – loose parts of chromosomes/translocation and can craete fusion genes (chromoplexy macroevelution a cancer cell in one cell division undergoes this, and chromothripsis- rare and worst disease outcome)
Somatic mutagenesis – point mutation in genes
Epigenetic heterogeneity - loss of cytosine methylation, increases plasticity, permitting cancer cells a greater degree of population diversity and enhancing the adaptive capacity of the overall tumor
What is the normal form of cancer evolution?
branching, not linear
What are the potential clinical impacts of knowledge of cancer evolution and heterogeneity?
Early disease detection – burden of cancer is prevalent, so early detection is very important, therapies are effective in some patients but not all – this is one way we could use evolutionary theory
Cancer therapy – trial structures you can build using evolutionary theory
Monitoring - can we monitor is real time how the cancer is progressing and therapy is performing
Risk stratification – getting at early tumors
Prevention – there may be things we can do throughout our lifespan to reduce risk of cancer , there may be very simple things we can do to help prevent cancer, e.g. small agents that have anti-tumour effects
Explain the promises of cancer therapy as a clinical implication from knowledge of cancer evolution and heterogeneity
Clonal therapy targeting clonal mutations to eradicate all tumour cells (such as targeted therapy or immunotherapy)
Preempt resistance
Adaptive therapy to chronically control disease
Explain the challenges of cancer therapy as a clinical implication from knowledge of cancer evolution and heterogeneity
Sampling strategy
Inevitable clonal monotherapy resistance
Bespoke combination therapies complicate toxicity and licensing
Explain the promises of monitoring as a clinical implication from knowledge of cancer evolution and heterogeneity
Bespoke monitoring on tumour-specific mutations
Explain the challenges of monitoring as a clinical implication from knowledge of cancer evolution and heterogeneity
High cost
Novel mutations or subclones may be missed
Early detection of relapse may not improve outcome
Explain the promises of early diagnosis and stratification as a clinical implication from knowledge of cancer evolution and heterogeneity
Identifying genetic changes meriting intervention
Explain the challenges of early diagnosis and stratification as a clinical implication from knowledge of cancer evolution and heterogeneity
Normal tissues contain canonical cancer mutations
Early diagnosis may not improve outcome
Explain the promises of prevention as a clinical implication from knowledge of cancer evolution and heterogeneity
Mutational signatures can suggest etiological factors that drive early tumorigenesis
Explain the challenges of prevention as a clinical implication from knowledge of cancer evolution and heterogeneity
Exogenous factors may not be preventable
Some tumors may not be preventable (such as those of children or young adults
What is the ideal clinical tool?
Robust measure of tumour heterogeneity satisfying the following criteria:
– Rapid and cost-effective
– Sampling should be minimally invasive or performed as part of resection and simple to handle e.g. can screen for lung cancer using nasal epithelium
– Comprehensive tumour sampling without any spatial biases
– Simple proxy biomarkers to assay ITH reliably
What are the sample options for evolution profiling
Single biopsy, Multi-region, Total tumour, CTC (circuating tumor cells), ctDNA
Explain the advantages and disadvantages of using a single biopsy for evolution profiling
Advantages :
Cheap
Minimally invasive
Disadvantages:
Under-represents heterogeneity
Explain the advantages and disadvantages of using a multi-region biopsy for evolution profiling
A:
Retains spatial information
D:
More invasive
Skill required to select regions
Explain the advantages and disadvantages of using a total-tumour biopsy for evolution profiling
A:
Global tumour sampling
D:
Destroys spatial information
Material lost to other pathological use
Explain the advantages and disadvantages of using a CTC biopsy for evolution profiling
A:
Allows serial monitoring
Intrinsically retains single cell information
D:
Expensive
Low sensitivity
Selection bias of cells by enrichment methods
Explain the advantages and disadvantages of using a ctDNA biopsy for evolution profiling
A:
Allows serial monitoring
Limited sample preparation
D:
Unknown how closely this reflects tumour hertogeneity
Explain evolutionary therapy stratagies
Targeting a clonal mutation:
-at the point of diagnosis give patient a drug that targets mutation (clonal targeting) this should kill the cl0one, but ten a new mutation/clone will begin to increase due to loss of competition, so to advance this:
Targeting combined clonal mutations:
-Combine clonal mutation agents
-Multiple clonal targeting an pre-existing subclonal resistance
-Limitation – combination of drugs the patiemt may not be able to tolerate them:
Adaptive therapy:
Less drugs, target and bring down the major clones (may not know about other clone) then monitor the patients progression using biomarkers, when you start to see the clone reducing or new clone starting you can stop treatment and see if the sensitive subclone suppresses the resistant out-competed subclone
What are the TRACERx trials
The TRACERx (TRAcking Cancer Evolution through therapy (Rx)) is a translational research study aimed at transforming our understanding of cancer evolution
– Lung, Melanoma, Prostate and Renal Cancer
What are some specific challenges in Therapy monitoring of ctDNA and CTCs
– Bias in ctDNA/CTCs - what you see in these markers may not actually be what’s happening in tumours
– De novo mutations arising subsequent to the sampling of the primary tumour
What is a major mutational signature in cancer
C-A mutations
Explain the tumour profile over a human life
In terms of mutation rate:
Spontaneous deaminatiin of 5meC stays cinstant from point if egg fertilisation
UV exposure starts before adolescence, reaches peak at adolecence and then stays constant (mutation rate higher than deamination)
Adolescence – smoking, but end up giving up, high exposure at this point though
WDG- whole genome doubling events, happen with age
Chemotherapy also gives signatures in a tumour profile
Theres also unknown exposures from things in your life that coukd lead to increased mutation rate
What are barriers to translation of Therapy monitoring and cancer prevention
- Toxicity to combination approaches
- Developing a comprehensive understanding of the complex mechanisms leading to resistance
- The challenge of somatic variation in normal tissues
- Limits of predictability due to the nature of cancer evolution
What are the deterministic processes and stochastic processes of cancer evolution?
deterministic:
Selection
stochastic:
Mutation and drift
What are the short and long term benefts of Developing new data-driven analytical approaches to cancer prediction
- Short-term:
– May benefit some patients by directing the development of a personalised cure - Longer-term:
– May benefit more patients by transforming cancer into a manageable chronic disease
