The Evolution of Cancer

Question 1

How error prone is asexual division of cells?

Answer 1

1-10 mutations per division

Question 2

How is tumour diversity limited?

Answer 2

Mutations alone lead to less variation than sexual reproduction

Question 3

What 3 factors impact the ability for somatic mutations to evolve?

Answer 3

Rate of mutation
Population turnover
Population size

Question 4

Name 3 similarities between single cell organismal evolution and somatic evolution

Answer 4

Asexual reproduction
Large population sizes
Short generation times

Question 5

What are the key differences between organismal evolution and somatic evolution?

Answer 5

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

Question 6

What are synonymous mutations (dS)?

Answer 6

They do not change the amino acid

Question 7

What are non-synonymous mutations (dN)?

Answer 7

They do change the amino acid

Question 8

What does it mean if there is more dN than dS?

Answer 8

There has been positive selection

Question 9

What does it mean if there is more dS than dN?

Answer 9

There has been negative selection

Question 10

What drives tumourigenesis?

Answer 10

When positive selection occurs (dN is higher than dS)

Question 11

In terms of selection, what are most cancer mutations?

Answer 11

Neutral

Question 12

Why is metastasis hard to detect?

Answer 12

Since we can only detect formed tumours

It may be moving through the blood or lymphatics but isn’t seen

Question 13

As you get older what do you develop, even in healthy patients?

Answer 13

More and bigger clones

Question 14

What are the 3 types of genetic diversity?

Answer 14

Mutation
Copy number changes
Structural aberrations

Question 15

Give 2 examples of genes which undergo copy number changes in cancer?

Answer 15

Myc and Her2

Question 16

What are the two types of structural aberrations?

Answer 16

Chromosomal translocations

Chromosomal deletions

Question 17

Give an example of a chromosomal translocation

Answer 17

9:22 in CML (BCR:Abl)

Question 18

Give an example of a chromosomal deletion

Answer 18

8p in breast and other cancers

Question 19

What does whole genome copy number changes do?

Answer 19

The genes double their genome

Question 20

What 3 ways can you measure genetic diversity in a tumour?

Answer 20

Deep sequencing
Single cell sequencing
Multi-region sequencing

Question 21

What is deep sequencing?

Answer 21

Uses next generation sequencing to measure mutant allele frequencies and copy number variations
You take one sample from the tumour

Question 22

What is the issue with deep sequencing?

Answer 22

Cannot locate where the different mutations are

Question 23

What is multi-region sequencing?

Answer 23

Next generation sequencing of different geographical regions of the tumour

Question 24

Advantage of deep sequencing

Answer 24

Cheep and quick

Question 25

What is the issue of multi-region sequencing?

Answer 25

Still cannot locate the exact location of the different mutations

Question 26

What is single cell sequencing?

Answer 26

Whole-genome amplification from a single cell and sequence it Means you know which cell it came from Ideally use lots of cells

Question 27

What is the issue with single cell sequencing?

Answer 27

It is expensive, however, is getting cheeper

Question 28

How does intra-tumour heterogeneity help detect evolutionary history?

Answer 28

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

Question 29

What are trunk mutations?

Answer 29

The mutations which are present in all of the samples

Question 30

What are branch mutations?

Answer 30

The mutations which are present in some but not all cells

Question 31

What are the 4 different models of tumour evolution?

Answer 31

Linear evolution Branched evolution Neutral evolution Punctuated evolution

Question 32

What is linear evolution?

Answer 32

Where a driver mutation provides a selection advantage and forms mutations in a chain

Question 33

Give the first model of tumour evolution

Answer 33

CRC progression | APC mutation -> K-Ras mutation -> Loss DCC -> Loss p53 -> other alterations

Question 34

What is branched evolution?

Answer 34

Clones diverge from a common ancestor and these subclones evolve in parallel because they offer increased fitness

Question 35

Why may multiple clones exist?

Answer 35

Cooperative interactions | Lack of competition

Question 36

Why do clones coexist?

Answer 36

They both have an advantage and therefore they aren't outcompeting each other

Question 37

What do fewer branches and longer trunks cause?

Answer 37

Better chemotherapy outcome

Question 38

How does neoadjuvant chemotherapy effect tumour landscape?

Answer 38

Provides the selective pressure for further evolution

Question 39

What is natural evolution?

Answer 39

There is an extreme case of branching evolution, but there is no fitness benefit in subclones during the life of the tumour

Question 40

What two pieces of evidence argue against neutral evolution?

Answer 40

Subclonal driver mutations | Convergent evolution

Question 41

What is convergent evolution?

Answer 41

The same mutation being selected in more than one subclone

Question 42

What is punctuated evolution?

Answer 42

Rapid bursts of change followed by stable clonal expansions | Huge genetic diversity allows complex karyotypes to be selected

Question 43

How is punctuated evolution different from linear or branched evolution?

Answer 43

Linear and branched are more associated around point mutations Punctuated evolution is more associated with copy number aberrations or chromosomal structural rearrangements

Question 44

4 factors which can cause punctuated evolution

Answer 44

Genome doubling Failed mitosis Chromothrypsis DNA replication error

Question 45

How does genome doubling induce punctuated evolution?

Answer 45

Failed cytokineses or endoreplication

Question 46

How does mitosis induce punctuated evolution?

Answer 46

Chromosomal gain/ loss/ rearrangement

Question 47

How does chromothrypsis induce punctuated evolution?

Answer 47

Chromosomes are shattered and repaired in a random order

Question 48

What is lower numbers of copy numbers associated with?

Answer 48

Disease free survival | A better prognosis