Cancer Heterogeneity Flashcards
What performs more than 90% of DNA sequencing?
Ilumina instruments
What is an exome?
The coding regions of DNA
How much of the genome is made up of exomes?
1%
What is cheaper than whole genome sequencing?
Exome sequencing - more targeted and manageable amounts of data produced
What is cancer heterogeneity?
Different cancer cells show distinct, individual properties
What different properties can cancer cells show?
Differences in:
- Morphology
- Metabolism
- Motility
- Proliferation
- Metastatic potential
- Gene expression
Between what can heterogeneity occur?
Between tumours (inter-tumour/patient) and within tumours (intra-tumour/patient)
What is generally the most genomically complex cancer?
Melanoma
What are actionable mutations?
A subset of mutations that have specific associated therapeutic implications
Give an example of an actionable mutation and its therapeutic indication
Colorectal cancer and Anti-EGFR
What does CRC rely on for proliferation?
Active EGFR signalling
How is EGR antagonised?
Binding of monoclonal antibodies to EGFR
Name some monoclonal antibodies used to antagonise EGR
- Cetuximab
- Panitumumab
Who is not eligable for anti-EGFR therapy?
Pts with KRAS or BRAF mutated tumours
How many patient of CRC are eligable?
~50%
Why are patient with BRAF or KRAS mutations not eligable?
Mutations in these genes mean they can act independently of EGFR signalling and induce resistance
What are truncal mutations?
Ubiquitous mutations found in all cells of the initial tumour
What are branch/subclonal mutations?
Mutations that are found regionally within a tumour
What do branch/subclonal mutations represent?
Secondary or local mutations within a tumour
Can branch mutations affect an already mutated gene?
Yes
What is temporal heterogeneity?
Differences in mutations acquired over time, comparing the end results to the initial founder clone
What is spatial heterogeneity?
Differences in tumour makeup within one tumour at the same point in time but across different locations within the tumour
What is a clone?
A homogenous group of cells with a common cell of origin
What is the cancer cell fraction (CCF)?
The percentage of cells that a mutation is found in within a single tumour
What CCF do trunk mutations have?
1 (i.e. 100%)
What are cells bearing a mutation with a CCF < 1 considered to be?
Subclones
What contributes to heterogeneity?
- Survival of the fittest/most resistant
- Selection pressures
What is the progression-free survival rate in melanoma pts treated with vemurafenib?
7 months
Why is the progression-free survival rate in melanoma pts treated with vemurafenib only 7 months?
There are additional BRAF mutations that are not inhibited by vemurafenib (V600E), as well as MAPK reactivation and overexpression of tyrosine kinase receptors
What increases the risk of a resistant clone being present in a neoplasm?
Diversity/High heterogeneity
Which 3 levels can diversity be at?
- Genetic
- Epigenetic
- Phenotypic
What 3 types of mutation are there?
- Driver
- Passenger
- Deleterious
What is a driver mutation?
Mutations that drive cells towards cancer
What is the link between driver mutations and oncogenesis?
They are casually implicated as they confer a growht advantage on the cancer cell
Is a driver mutations required for maintenance of the final cancer?
No, but often it is still used
What is a passenger mutation?
A mutation that doesn’t confer a growth advantage and does not contribute to cancer development
Why are passenger mutations often found in cancer genomes?
Somatic mutations without functional consequences often occur in cell division
What are deleterious mutations?
Mutations that impair cell survival
Are deleterious mutations found within the cancer gemome? Why?
No, because they are subject to negative selection
What is the clinical consequence of branch mutations in driver genes?
Clinical decision on treatment based on a single biopsy so treatment indicated wont cover all the mutations across the whole tumour.
Is multiregional sequencing feasible in standard clinical practice?
No
How do we prevent resistance?
Combination therapy
