Cancer Heterogeneity

Question 1

What performs more than 90% of DNA sequencing?

Answer 1

Ilumina instruments

Question 2

What is an exome?

Answer 2

The coding regions of DNA

Question 3

How much of the genome is made up of exomes?

Answer 3

1%

Question 4

What is cheaper than whole genome sequencing?

Answer 4

Exome sequencing - more targeted and manageable amounts of data produced

Question 5

What is cancer heterogeneity?

Answer 5

Different cancer cells show distinct, individual properties

Question 6

What different properties can cancer cells show?

Answer 6

Differences in:

• Morphology
• Metabolism
• Motility
• Proliferation
• Metastatic potential
• Gene expression

Question 7

Between what can heterogeneity occur?

Answer 7

Between tumours (inter-tumour/patient) and within tumours (intra-tumour/patient)

Question 8

What is generally the most genomically complex cancer?

Answer 8

Melanoma

Question 9

What are actionable mutations?

Answer 9

A subset of mutations that have specific associated therapeutic implications

Question 10

Give an example of an actionable mutation and its therapeutic indication

Answer 10

Colorectal cancer and Anti-EGFR

Question 11

What does CRC rely on for proliferation?

Answer 11

Active EGFR signalling

Question 12

How is EGR antagonised?

Answer 12

Binding of monoclonal antibodies to EGFR

Question 13

Name some monoclonal antibodies used to antagonise EGR

Answer 13

• Cetuximab

- Panitumumab

Question 14

Who is not eligable for anti-EGFR therapy?

Answer 14

Pts with KRAS or BRAF mutated tumours

Question 15

How many patient of CRC are eligable?

Answer 15

~50%

Question 16

Why are patient with BRAF or KRAS mutations not eligable?

Answer 16

Mutations in these genes mean they can act independently of EGFR signalling and induce resistance

Question 17

What are truncal mutations?

Answer 17

Ubiquitous mutations found in all cells of the initial tumour

Question 18

What are branch/subclonal mutations?

Answer 18

Mutations that are found regionally within a tumour

Question 19

What do branch/subclonal mutations represent?

Answer 19

Secondary or local mutations within a tumour

Question 20

Can branch mutations affect an already mutated gene?

Answer 20

Yes

Question 21

What is temporal heterogeneity?

Answer 21

Differences in mutations acquired over time, comparing the end results to the initial founder clone

Question 22

What is spatial heterogeneity?

Answer 22

Differences in tumour makeup within one tumour at the same point in time but across different locations within the tumour

Question 23

What is a clone?

Answer 23

A homogenous group of cells with a common cell of origin

Question 24

What is the cancer cell fraction (CCF)?

Answer 24

The percentage of cells that a mutation is found in within a single tumour

Question 25

What CCF do trunk mutations have?

Answer 25

1 (i.e. 100%)

Question 26

What are cells bearing a mutation with a CCF < 1 considered to be?

Answer 26

Subclones

Question 27

What contributes to heterogeneity?

Answer 27

- Survival of the fittest/most resistant | - Selection pressures

Question 28

What is the progression-free survival rate in melanoma pts treated with vemurafenib?

Answer 28

7 months

Question 29

Why is the progression-free survival rate in melanoma pts treated with vemurafenib only 7 months?

Answer 29

There are additional BRAF mutations that are not inhibited by vemurafenib (V600E), as well as MAPK reactivation and overexpression of tyrosine kinase receptors

Question 30

What increases the risk of a resistant clone being present in a neoplasm?

Answer 30

Diversity/High heterogeneity

Question 31

Which 3 levels can diversity be at?

Answer 31

- Genetic - Epigenetic - Phenotypic

Question 32

What 3 types of mutation are there?

Answer 32

- Driver - Passenger - Deleterious

Question 33

What is a driver mutation?

Answer 33

Mutations that drive cells towards cancer

Question 34

What is the link between driver mutations and oncogenesis?

Answer 34

They are casually implicated as they confer a growht advantage on the cancer cell

Question 35

Is a driver mutations required for maintenance of the final cancer?

Answer 35

No, but often it is still used

Question 36

What is a passenger mutation?

Answer 36

A mutation that doesn't confer a growth advantage and does not contribute to cancer development

Question 37

Why are passenger mutations often found in cancer genomes?

Answer 37

Somatic mutations without functional consequences often occur in cell division

Question 38

What are deleterious mutations?

Answer 38

Mutations that impair cell survival

Question 39

Are deleterious mutations found within the cancer gemome? Why?

Answer 39

No, because they are subject to negative selection

Question 40

What is the clinical consequence of branch mutations in driver genes?

Answer 40

Clinical decision on treatment based on a single biopsy so treatment indicated wont cover all the mutations across the whole tumour.

Question 41

Is multiregional sequencing feasible in standard clinical practice?

Answer 41

No

Question 42

How do we prevent resistance?

Answer 42

Combination therapy