Biology 3594A Lecture Notes - Lecture 14: Multiplex Polymerase Chain Reaction, Somatic Hypermutation, Epitope
13 May 2018
School
Department
Course
Professor
WGS –you would know where mutations are in the genome, single nucleotide resolution
Detected: damage (what type?)
Epitope on an antigen, elicits a mutation response in ELISA
Discovery –not a specific locus or bp, very broad
Validation/Confirmation –very specific (cast assays, multiplex PCR)
What is the aggregate mutation burden/load in that tumour? Some are ultrahypermutation or hypermutation type of cancers
They want to classify these –perhaps you treat each type differently, with different drugs, different targets
In the study they have 3 levels of analysis
Then gather up hypermutation and look for driver mutations –genes in the tumours that have mutations that drive them to mutate stuff, be very fit
Other mutations tag along –passenger mutations
They will have a signature –base that was hit, type of change: recognizable
If you know the driver mutation and the signature and learn about how they occur, we can give this info to people in pharmace utical industries and they can be the
therapeutic targets
Clusters –phenotypes
Certain tumours will have certain drivers, certain signatures of mutation
When we design a particular therapy it can be for that mutation and that kind of tumour
Can better diagnose in the clinic by clusters, and then target shutting that specific type down
Paper is about what they learn about cluster 1 and 2 and 3 (there are others but focus on these)
Why do they want to do this: want to understand the mutational processes so we can stop them
Want to do better diagnoses and prognoses
Want to know what therapeutic agents to use
Particularly interested in hypermutable and ultrahypermutable –grow very fast and are complex to treat later on so want to catch them early
Diagram of all complexities in mutagenesis
Understand how mutations arise
Left: start with the genome, haven’t acquired any mutations unless inherited. But can be an intrinsic or endogenous mutagen t hat creates mutation
Could go to damage –repaired or goes to apoptosis, or gets replicated and end up on other side where we might see it
Left: everything driving backwards through repair and not getting replicated
Right: mutations and seen in subsequent cells, from damage to mutation over the line
POLD1 and POLE –polymerases that have error prone natures when they are mutated –these mutations can be drivers
They are operating during replication and increase mutation into the high levels that you see on the right side
Far right: high levels of mutation (hyper and ultrahyper)
They drive phenotypes of excessive division and replication
The more fit the tumour cells are the more mutation burden they cause
A few drivers and many many passengers
Figure out who is the driver and who are the passengers
Penetrance –phenotype we can see like excessive growth in tumours
Having a positive selection effect
Purifying selection –was a mutation, but wasn’t fit so won’t see it again
Dynamics –important descriptor
Over time the profile of mutations is changing, growing, becoming more complex
Something that is changing in time and therapies maybe need to change in time as well
What is a driver at one point could be overshadowed by another mutation that pops up later on that is a better driver
If we take all the tumours and look at total burden (mutations/bp)
Low burden vs hyper vs ultrahyper
What cancers have that and what can we do?
In children tends to be in CNS
Classify tumours as low and hyper and ultrahyper –new definition and good thresholds (major contribution by the paper)
Also figured that genes with mutations change
In the Ultrahyper is POL genes and mismatch repair (MMR)
Adults have diff profile of how many tumours in low, hyper and ultrahyper
Melanoma and lung not CNS like in children –affects diagnosis, prognosis, therapies
Can put in red whether they have microsatellite instability
Lec 14 Hypermutation
May 13, 2018
2:45 PM
3594 Page 1
Document Summary
Wgs you would know where mutations are in the genome, single nucleotide resolution. Epitope on an antigen, elicits a mutation response in elisa. Discovery not a specific locus or bp, very broad. Validation/confirmation very specific (cast assays, multiplex pcr) Some are ultrahypermutation or hypermutation type of cancers. They want to classify these perhaps you treat each type differently, with different drugs, different targets. In the study they have 3 levels of analysis. Then gather up hypermutation and look for driver mutations genes in the tumours that have mutations that drive them to mutate stuff, be very fit. They will have a signature base that was hit, type of change: recognizable. If you know the driver mutation and the signature and learn about how they occur, we can give this info to people in pharmace utical industries and they can be the therapeutic targets. Certain tumours will have certain drivers, certain signatures of mutation.
