Biology 3594A Lecture Notes - Lecture 15: Genotoxicity, Somatic Hypermutation, Left Alternative
13 May 2018
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HIGHLIGHTS - STUDY FROM THE PAPER, IT’S NOT IN THE PPT.
Pay attention to the words used.
2 boxes = today’s lecture
Final exp’s look at mtuation signatures and how they change in the prominence of the tumour
Early or late, how many cells in the tumour have the mutation
Relevant to patient survival
POWER OF NGS
In targetted gene panel, in whole exome, in whole genome
Drivers in the 3 clusters are hypermutation related to driver mutations and are REPLICATION DEPENDENT
How do they cluster?
In all cancers and mutations present, they are clustered based on similarity of mutation in a particular context
There are 96 contexts based on nucleotide patterns
Mutational load/burden = aggregate # of mutations there
Coverage/read depth = # of times a base is called
If the tumour has a subpopulation with a big mutational change, sequencing data will be read many times
If in the smaller subpopoulation, less reads
100reads may share a particular change, could be an earlier mutation that arose, possibly a driver
Less reads indicative of later mutation
Variant allele fraction = how many reads have the mutation
High = early
Low = recent
mid = where driver mutations arose
NGS adds another dimension to sequencing that is time/chronology
survivorship not necessarily associated w mutation burden
Clustering is based on these data
When you analyze as single trinucleotides you can come up with signatures –over 30 cancer signatures, figure out diagnosis/prognosis/ability to respond/what kind of
chemotherapeutic drugs to use
Tumours have diff cell pops that are diff in size depending on when the mutation arose
Left list: patients
Significant signatures of mutation, can find other signature mutations arising
Can identify that it is in the germline –important to inform family
Have the mutations ever been seen before? Are they in a database? Are there successful treatments for this?
Treatments are about halting cell division
Immune and antibody therapies are popular right now –antibodies are very effective
PET scan looks at high metabolism of cancers
Summary: nice paper from basic science to translational stuff
Humans put chemicals into the water
Try to figure out if the species in the ecosystems are upset by this
Is there something in the environment that is DNA damaging?
This paper is investigative report from a journal with impact factor 4
Short paper
Says that they think the stuff in sewage and waste water is damaging to ecosystems
Carp is important in freshwater –economic and ecosystem issues when you cause DNA damage and cell death
No mutation detection assay, has genotoxicity (DNA damage)
Looks at cell death through apoptosis
Going to repeat comet and MN assay as DNA damaging and genotoxic
Tunel –strand breaks detection
Two pronged –know about genotoxicity, cytoxicity
Carp is model organism
Representative of many things in environment –pharmaceutical agents that humans put into the water
Estradiol changes sex of organisms and changes endocrine function –does it damage DNA?
Sample of environmental biomonitoring protocol
Estradiol aka E2
This is just the beginning, sentinel for so many other compounds that aren’t regulated
Lec 15 Hypermutation and 17-B Estradiol Exposure
May 13, 2018
2:49 PM
3594 Page 1
Document Summary
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