Cancer Heterogeneity Flashcards

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1
Q

What performs more than 90% of DNA sequencing?

A

Ilumina instruments

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2
Q

What is an exome?

A

The coding regions of DNA

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3
Q

How much of the genome is made up of exomes?

A

1%

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4
Q

What is cheaper than whole genome sequencing?

A

Exome sequencing - more targeted and manageable amounts of data produced

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5
Q

What is cancer heterogeneity?

A

Different cancer cells show distinct, individual properties

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6
Q

What different properties can cancer cells show?

A

Differences in:

  • Morphology
  • Metabolism
  • Motility
  • Proliferation
  • Metastatic potential
  • Gene expression
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7
Q

Between what can heterogeneity occur?

A

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

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8
Q

What is generally the most genomically complex cancer?

A

Melanoma

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9
Q

What are actionable mutations?

A

A subset of mutations that have specific associated therapeutic implications

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10
Q

Give an example of an actionable mutation and its therapeutic indication

A

Colorectal cancer and Anti-EGFR

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11
Q

What does CRC rely on for proliferation?

A

Active EGFR signalling

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12
Q

How is EGR antagonised?

A

Binding of monoclonal antibodies to EGFR

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13
Q

Name some monoclonal antibodies used to antagonise EGR

A
  • Cetuximab

- Panitumumab

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14
Q

Who is not eligable for anti-EGFR therapy?

A

Pts with KRAS or BRAF mutated tumours

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15
Q

How many patient of CRC are eligable?

A

~50%

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16
Q

Why are patient with BRAF or KRAS mutations not eligable?

A

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

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17
Q

What are truncal mutations?

A

Ubiquitous mutations found in all cells of the initial tumour

18
Q

What are branch/subclonal mutations?

A

Mutations that are found regionally within a tumour

19
Q

What do branch/subclonal mutations represent?

A

Secondary or local mutations within a tumour

20
Q

Can branch mutations affect an already mutated gene?

A

Yes

21
Q

What is temporal heterogeneity?

A

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

22
Q

What is spatial heterogeneity?

A

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

23
Q

What is a clone?

A

A homogenous group of cells with a common cell of origin

24
Q

What is the cancer cell fraction (CCF)?

A

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

25
Q

What CCF do trunk mutations have?

A

1 (i.e. 100%)

26
Q

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

A

Subclones

27
Q

What contributes to heterogeneity?

A
  • Survival of the fittest/most resistant

- Selection pressures

28
Q

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

A

7 months

29
Q

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

A

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

30
Q

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

A

Diversity/High heterogeneity

31
Q

Which 3 levels can diversity be at?

A
  • Genetic
  • Epigenetic
  • Phenotypic
32
Q

What 3 types of mutation are there?

A
  • Driver
  • Passenger
  • Deleterious
33
Q

What is a driver mutation?

A

Mutations that drive cells towards cancer

34
Q

What is the link between driver mutations and oncogenesis?

A

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

35
Q

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

A

No, but often it is still used

36
Q

What is a passenger mutation?

A

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

37
Q

Why are passenger mutations often found in cancer genomes?

A

Somatic mutations without functional consequences often occur in cell division

38
Q

What are deleterious mutations?

A

Mutations that impair cell survival

39
Q

Are deleterious mutations found within the cancer gemome? Why?

A

No, because they are subject to negative selection

40
Q

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

A

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

41
Q

Is multiregional sequencing feasible in standard clinical practice?

A

No

42
Q

How do we prevent resistance?

A

Combination therapy