Lectures 7&8 - Cancer evolution

Question 1

Whats the difference between a benign tumour and a malignant tumour

Answer 1

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)

Question 2

What are possible reasons for a higher rate of cancer in humans than other species?

Answer 2

– 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

Question 3

Explain the Somatic mutation theory (SMT) of cancer

Answer 3

• 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)

Question 4

What is micro-evolution

Answer 4

Change in the genetic composition that occurs over time in a population – e.g. Antibiotic resistance

Question 5

What is macro-evolution

Answer 5

Major evolutionary change at or above the level of the species

–e.g. Speciation, generating a new species

Question 6

What is somatic evolution?

Answer 6

• 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

Question 7

Define a Clone

Answer 7

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.

Question 8

Define Neoplastic progression

Answer 8

the somatic evolutionary process by which normal tissue changes into malignant (cancerous) tissue

Question 9

What does the The Shannon diversity index tell you

Answer 9

How diverse the species in a given community are

Question 10

explain how clonal diversity measurements may have utility towards personalised cancer evolution forecasts

Answer 10

Number and how different clones are directly correlate with individual risk of having cancer

Question 11

What is a driver mutation

Answer 11

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

Question 12

What is a passenger mutation

Answer 12

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

Question 13

What mechanisms generate diversity

Answer 13

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

Question 14

What is the normal form of cancer evolution?

Answer 14

branching, not linear

Question 15

What are the potential clinical impacts of knowledge of cancer evolution and heterogeneity?

Answer 15

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

Question 16

Explain the promises of cancer therapy as a clinical implication from knowledge of cancer evolution and heterogeneity

Answer 16

Clonal therapy targeting clonal mutations to eradicate all tumour cells (such as targeted therapy or immunotherapy)

Preempt resistance

Adaptive therapy to chronically control disease

Question 17

Explain the challenges of cancer therapy as a clinical implication from knowledge of cancer evolution and heterogeneity

Answer 17

Sampling strategy

Inevitable clonal monotherapy resistance

Bespoke combination therapies complicate toxicity and licensing

Question 18

Explain the promises of monitoring as a clinical implication from knowledge of cancer evolution and heterogeneity

Answer 18

Bespoke monitoring on tumour-specific mutations

Question 19

Explain the challenges of monitoring as a clinical implication from knowledge of cancer evolution and heterogeneity

Answer 19

High cost

Novel mutations or subclones may be missed

Early detection of relapse may not improve outcome

Question 20

Explain the promises of early diagnosis and stratification as a clinical implication from knowledge of cancer evolution and heterogeneity

Answer 20

Identifying genetic changes meriting intervention

Question 21

Explain the challenges of early diagnosis and stratification as a clinical implication from knowledge of cancer evolution and heterogeneity

Answer 21

Normal tissues contain canonical cancer mutations

Early diagnosis may not improve outcome

Question 22

Explain the promises of prevention as a clinical implication from knowledge of cancer evolution and heterogeneity

Answer 22

Mutational signatures can suggest etiological factors that drive early tumorigenesis

Question 23

Explain the challenges of prevention as a clinical implication from knowledge of cancer evolution and heterogeneity

Answer 23

Exogenous factors may not be preventable

Some tumors may not be preventable (such as those of children or young adults

Question 24

What is the ideal clinical tool?

Answer 24

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

Question 25

What are the sample options for evolution profiling

Answer 25

Single biopsy, Multi-region, Total tumour, CTC (circuating tumor cells), ctDNA

Question 26

Explain the advantages and disadvantages of using a single biopsy for evolution profiling

Answer 26

Advantages :
Cheap
Minimally invasive

Disadvantages:
Under-represents heterogeneity

Question 27

Explain the advantages and disadvantages of using a multi-region biopsy for evolution profiling

Answer 27

A:
Retains spatial information

D:
More invasive
Skill required to select regions

Question 28

Explain the advantages and disadvantages of using a total-tumour biopsy for evolution profiling

Answer 28

A:
Global tumour sampling

D:
Destroys spatial information
Material lost to other pathological use

Question 29

Explain the advantages and disadvantages of using a CTC biopsy for evolution profiling

Answer 29

A:
Allows serial monitoring
Intrinsically retains single cell information

D:
Expensive
Low sensitivity
Selection bias of cells by enrichment methods

Question 30

Explain the advantages and disadvantages of using a ctDNA biopsy for evolution profiling

Answer 30

A:
Allows serial monitoring
Limited sample preparation

D:
Unknown how closely this reflects tumour hertogeneity

Question 31

Explain evolutionary therapy stratagies

Answer 31

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

Question 32

What are the TRACERx trials

Answer 32

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

Question 33

What are some specific challenges in Therapy monitoring of ctDNA and CTCs

Answer 33

– 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

Question 34

What is a major mutational signature in cancer

Answer 34

C-A mutations

Question 35

Explain the tumour profile over a human life

Answer 35

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

Question 36

What are barriers to translation of Therapy monitoring and cancer prevention

Answer 36

• 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

Question 37

What are the deterministic processes and stochastic processes of cancer evolution?

Answer 37

deterministic:
Selection

stochastic:
Mutation and drift

Question 38

What are the short and long term benefts of Developing new data-driven analytical approaches to cancer prediction

Answer 38

• 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