Cancer Evolution

Question 1

what features are shared by both natural selection and cancer?

Answer 1

• variation in the population
• traits ust be heritable
• affect survival/reproduction fitness
• clonal expansion

Question 2

what are some possible reasons that humans have more cancer than other species?

Answer 2

• long post reproductive lifespan
• mis-matched to risk factors generated by civilisation
• highly invasive placentas produced by stem cells pre adapted to metastasis1

Question 3

why is clincal cancer not even more common?

Answer 3

we are not great at detecting it and the cancer lottery (a combination of DNA damagin exposures, modulators of risk and chance all contribute to wether mutations lead to cancer)

Question 4

what is the somatic mutation theory (SMT) of cancer?

Answer 4

cancer begins with a genetic change in a single cell that passes it on to its progeny thereby creating 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 sufficiently to cause death of the host
- cancer is mediated by somatic evolution at the level of the cell

Question 5

what is microevolution?

Answer 5

change in the genetic composition that occurs over time in a population

Question 6

what is macroevolution?

Answer 6

major evolutionary change at or above the level of a species

Question 7

what is the punctuated pattern of evolution

Answer 7

discontinuous acquisition of mutations over time with periods of relative stasis. mutations may be acquired in distinct patterns and be co-located, or can be distributed across the genome
(short periods of rapid evolution followed by longer periods of stasis in which no change occurs)

Question 8

what is gradualism

Answer 8

a policy of gradual reform rather than sudden change or revolution

Question 9

what is gradual evolution

Answer 9

an iterative pettern of mutation acquisition and selection over time

Question 10

what is somatic evolution?

Answer 10

accumulation of (epi)mutations in somatic cells of your body during your lifetime
these occur in normal tissues and increased with age/ risk exposures
they may effect the fitness of those cells and lead to positive selection of mutant clones

Question 11

what is neoplastic progression?

Answer 11

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

Question 12

what is a clone?

Answer 12

set of cells that all descend from a common ancestor cell -usually distinguished through heritances of distinctive genetic lesions that occured in the ancestor cell

Question 13

what is a clone?

Answer 13

set of cells that all descend from a common ancestor cell -usually distinguished through heritances of distinctive genetic lesions that occured in the ancestor cell

Number of clones, measuring how different they are can directly correlate with individual risk of developing cancer in your l lifetime.

Question 14

what are driver mutations?

Answer 14

mutations that give a selective advantage to a clone in its microenvironment, through either increasing its survival or reproduction. driver mutations tend to cause clonal expansion

Question 15

what are passenger mutations?

Answer 15

mutations that have no effect on the fitness of the clon but may be associated with a clonal expansion because it occurs in the same genome with a driver mutations. this is know as a hitchhiker in evolutionary biology

Question 16

what is chromoplexy?

Answer 16

disordered recombination of the chromosome in one cell division - causes genetic material from one or more chromosomes to become scrambled as multiple strands of DNA are broken and ligated to each other in a new configuration.

Question 17

what is chromothripsis?

Answer 17

a mutational process by which up to thousands of clustered chromosomal rearrangements occur in a single event in localised and confined genomic regions in one or a few chromosomes - a chromosome is shattered and abhorrantly stictched back together

Question 18

what is the classic model of cancer evolution?

Answer 18

linear successive clonal expansion, driven by the accumulation of genomic lesions that are preferentially selected by the tumour environment

Question 19

give four mechanisms of diversity
in the genetic makeup of tumour cells

Answer 19

• numerical chromosomal instability
• somatic mutagenesis
• structural chromosomal instability (eg chromoplexy, chromothripsis)
• epigenetic heterogeneity

Question 20

rather than linear evolution, what type of evolution more accurately describes that seen in cancer?

Answer 20

branching evolution

Question 21

what are the promises and challenges in translating insights into tumour evolution to help therapy

Answer 21

Promises;
* clonal therapy targeting clonal mutations to eradicate all tumor cells (targeted therapy, immunotherapy)
* preempt resistance
* adaptive therapy to chronically control disease
Challenges;
* sampling stretegy
* inevitable clonal monotherapy resistance
* bespoke combination therapies complicate toxicity and licensing

Question 22

what are the promises and challenges in translating insights into tumour evolution to monitoring?

Answer 22

promises;
* bespoke monitoring based on tumor-specific mutations

challenges;
* high cost
* novel mutations of subclones may be missed
* early detection of relapse may not improve outcome

Question 23

what are the promises and challenges in translating insights into tumour evolution in early diagnosis and stratification

Answer 23

promises;
* identify changes meriting intervention

challenges;
* normal tissues contain canonical cancer mutations
* early diagnosis may not improve outcome

Question 24

what are the promises and challenges in translating insights into tumour evolution in prevention

Answer 24

promises;
* mutational signatures can suggest etiological factors that drive early tumorigenesis

challenges;
* exogenous factors may not be preventable
* some tumours may not be preventable (such as those of children and young adults)

Question 25

what are 4 features of the ideal clinical tool?

Answer 25

• rapid and cost effective
• sampling minimally invasive or performed as part of a resection and simple to handle
• comprehensive tumor sampling without any spatial bias
• simple proxy biomarkers to assay ITH reliably

Question 26

what are the advantages and disadvantages of single biopsies?

Answer 26

advantages;
* cheap
* minimally invasive

disadvantages;
* under represents heterogeneity

Question 27

what are the advantages and disadvantages of multiregion biopsies

Answer 27

ad; retains spatial information
disad; more invasive, skill required to select regions

Question 28

what are the advantages and disadvantages to total tumour sampling

Answer 28

ad; global tumour sampling
disad; destroys spatial information, material lost to other pathological use

Question 29

what are the advantages and disadvantages to total tumour sampling

Answer 29

ad; global tumour sampling
disad; destroys patial information, material lost to other pathological use

Question 30

what are the advantages and disadvantages to sampling CTCs

(circulating tumour cells)

Answer 30

advantages;
* allows serial monitoring
* intrinsically retains single cell information

disadvantages;
* expensive,
* low sensitivity,
* selection bias of cells by enrishment methods

Question 31

what are the advantages and disadvantages of sampling ctDNA

(circulating tumour DNA)

Answer 31

advantages;
* allows serial monitoring
* limited sample preparation

disadvantages;
* unknown how closely this reflects tumor heterogeneity

Question 32

what barriers are there to translating insights from cancer evolution to clinical practice?

Answer 32

 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 33

what is a subclone?

Answer 33

cells originating from a more recent cell than the most recent common ancestor. these will possess both the clonal mutations and also the subclonal mutations that are private to that subclone

Question 33

what is a subclone?

Answer 33

cells originating from a more recent cell than the most recent common ancestor. these will possess both the clonal mutations and also the subclonal mutations that are private to that subclone

Question 34

how does adaptive subclonal targeting work

Answer 34

Want to target major clones, then monitor patients progression (using biomarkers), see clone declining then interrupt the therapy before elimination of major clone competition, minimising the emerging resistant clone, using the other cancer to hold them in check
this treatment interuption allows the resistant

Question 35

What are the limits of predictability in cancer evolution?
Deterministic and stochastic processes

Selection, mutation, drift

Answer 35

hindered by spatial tumour structures
different selection pressures
clonal competition
epistasis
genetic load
temporal variability
spatial variability
Robustness against mutations
Many distins mutational mechanisms
Regional differences in mutational rates across the genome
Population bottlenecks
variability with fitness advantage
Variability with population size and spatial structures

Question 36

What is epistasis?

Answer 36

a circumstance where the expression of one gene is modified (e.g., masked, inhibited or suppressed) by the expression of one or more other genes

Question 37

how does epistasis effect tumours?

Answer 37

Genomic alterations in tumors affect the fitness of tumor cells, controlling how well they replicate and survive compared to other cells. The landscape of tumor fitness is shaped by epistasis. Epistasis occurs when the contribution of gene alterations to the total fitness is non-linear

Question 38

describe the acquisition of mutations in colorectal carcinoma from adenoma

Answer 38

Transformed stem cells are formed after mutation of both APC alleles that results in constant activation of the Wnt pathway, leading to unrestricted cell division. After this initiating mutation, other typical genes affected by mutations are KRAS or BRAFs (both are essential activating components of the EGF pathway), or genes responsible for maintaining epithelial traits which results in the induction of epithelial-mesenchymal transition. The loss of the genome guarding TP53 results in chromosome instability, the genome will be severely damaged, and the tumour produces metastases throughout the body. The sequential mutations in these and other genes was first suggested by Vogelstein and Fearon