The Evolution of Cancer Flashcards
How error prone is asexual division of cells?
1-10 mutations per division
How is tumour diversity limited?
Mutations alone lead to less variation than sexual reproduction
What 3 factors impact the ability for somatic mutations to evolve?
Rate of mutation
Population turnover
Population size
Name 3 similarities between single cell organismal evolution and somatic evolution
Asexual reproduction
Large population sizes
Short generation times
What are the key differences between organismal evolution and somatic evolution?
Single celled organisms have typically already evolved to peak fitness, therefore most mutations will be deleted
In multicellular organisms, they have evolved for the fitness of the organism, not the cell
What are synonymous mutations (dS)?
They do not change the amino acid
What are non-synonymous mutations (dN)?
They do change the amino acid
What does it mean if there is more dN than dS?
There has been positive selection
What does it mean if there is more dS than dN?
There has been negative selection
What drives tumourigenesis?
When positive selection occurs (dN is higher than dS)
In terms of selection, what are most cancer mutations?
Neutral
Why is metastasis hard to detect?
Since we can only detect formed tumours
It may be moving through the blood or lymphatics but isn’t seen
As you get older what do you develop, even in healthy patients?
More and bigger clones
What are the 3 types of genetic diversity?
Mutation
Copy number changes
Structural aberrations
Give 2 examples of genes which undergo copy number changes in cancer?
Myc and Her2
What are the two types of structural aberrations?
Chromosomal translocations
Chromosomal deletions
Give an example of a chromosomal translocation
9:22 in CML (BCR:Abl)
Give an example of a chromosomal deletion
8p in breast and other cancers
What does whole genome copy number changes do?
The genes double their genome
What 3 ways can you measure genetic diversity in a tumour?
Deep sequencing
Single cell sequencing
Multi-region sequencing
What is deep sequencing?
Uses next generation sequencing to measure mutant allele frequencies and copy number variations
You take one sample from the tumour
What is the issue with deep sequencing?
Cannot locate where the different mutations are
What is multi-region sequencing?
Next generation sequencing of different geographical regions of the tumour
Advantage of deep sequencing
Cheep and quick
What is the issue of multi-region sequencing?
Still cannot locate the exact location of the different mutations
What is single cell sequencing?
Whole-genome amplification from a single cell and sequence it
Means you know which cell it came from
Ideally use lots of cells
What is the issue with single cell sequencing?
It is expensive, however, is getting cheeper
How does intra-tumour heterogeneity help detect evolutionary history?
If there is a group of cells, and most of them have one or two mutations which are the same, these are typically the starter mutations
What are trunk mutations?
The mutations which are present in all of the samples
What are branch mutations?
The mutations which are present in some but not all cells
What are the 4 different models of tumour evolution?
Linear evolution
Branched evolution
Neutral evolution
Punctuated evolution
What is linear evolution?
Where a driver mutation provides a selection advantage and forms mutations in a chain
Give the first model of tumour evolution
CRC progression
APC mutation -> K-Ras mutation -> Loss DCC -> Loss p53 -> other alterations
What is branched evolution?
Clones diverge from a common ancestor and these subclones evolve in parallel because they offer increased fitness
Why may multiple clones exist?
Cooperative interactions
Lack of competition
Why do clones coexist?
They both have an advantage and therefore they aren’t outcompeting each other
What do fewer branches and longer trunks cause?
Better chemotherapy outcome
How does neoadjuvant chemotherapy effect tumour landscape?
Provides the selective pressure for further evolution
What is natural evolution?
There is an extreme case of branching evolution, but there is no fitness benefit in subclones during the life of the tumour
What two pieces of evidence argue against neutral evolution?
Subclonal driver mutations
Convergent evolution
What is convergent evolution?
The same mutation being selected in more than one subclone
What is punctuated evolution?
Rapid bursts of change followed by stable clonal expansions
Huge genetic diversity allows complex karyotypes to be selected
How is punctuated evolution different from linear or branched evolution?
Linear and branched are more associated around point mutations
Punctuated evolution is more associated with copy number aberrations or chromosomal structural rearrangements
4 factors which can cause punctuated evolution
Genome doubling
Failed mitosis
Chromothrypsis
DNA replication error
How does genome doubling induce punctuated evolution?
Failed cytokineses or endoreplication
How does mitosis induce punctuated evolution?
Chromosomal gain/ loss/ rearrangement
How does chromothrypsis induce punctuated evolution?
Chromosomes are shattered and repaired in a random order
What is lower numbers of copy numbers associated with?
Disease free survival
A better prognosis
