Cancer Hetergeneity Flashcards
Why is exome sequencing cheaper than whole genome sequencing?
Exomes make up the coding regions of DNA and only make up 1% of the genome
-therefore exome sequencing is cheaper and more manageable
What are some distinct properties that cancer cells show?
Morphology Metabolism Proliferation Metastatic potential Gene expression Genetic alterations
What is inter-patient heterogeneity?
A subdivision of dividing cancer by histology, the driver of mutation and origin
-each patient has a unique cancer because of its genetic and genomic features
What does inter-patient heterogeneity have consequences on and why?
Treatment
Only a subset of individuals bear alterations compatible with response to a drug treatment
What are trunk and branch mutations?
Trunk mutations are ubiquitous, and present in the initial tumour
Branch mutations are regional and represent secondary and local mutations. Different mutations can affect the same gene (convergent evolution)
Explain the branching evolution of a cancer
Trunk contains all of the original initiator events
Internal branches are the first clones to initiate heterogeneity
Terminal branches are current active clones
What are clones?
A homogenous group of cells sharing the same ancestor
Which type of mutation has a cancer cell fraction of 100% within a tumour?
Trunk/founder mutations
What does it mean if a mutation has a cancer cell fraction of anything less than one?
The tumour cells with these mutations are sub-clones
What shales heterogeneity?
The fittest clone survives, where therapy is the selective pressure
What are the therapeutic implications of heterogeneity?
Get resistance
Give an example of where resistance can be seen due to tumour heterogeneity
Panitumumab and cetuximab inhibit Ras, inhibiting growth of CRC
Resistance occurs due to acquisition of KRas mutations (however the mutations may have already existed)
Give an example of how resistance can occur in melanoma
Vemurafenib inhibits BRAF
Get further mutations to BRAF leading to MAPK deactivation via N-Ras and over-eps region of tyrosine kinase receptors
Give features of driver mutations
Implicated in omcogenesis
Confer a growth advantage in the cancer cell
Positively selected
May not be required for maintenance of the final cancer though often is
Give features of passenger mutations
Do not contribute to cancer development
Found within cancer genomes because somatic mutations without functional consequences often occur during cell division but are not selected
