L12 - Chromosomes and cancer 2 Flashcards
(27 cards)
hown many events are required for solid tumors to become malignant
6-8
why are solid tuors highly aneuploid
abnormal chromosome segregation in mitosis/cell division
- deletions and loss of TSGs are also key charecteristics
when was the first translocation in solid tumors disocvered and why was this shocking
2005 - fusion of genes involving serine proteases and transcription family
found in aprox 50% of prostate cancers
= translocations were thought to be present only in haem/nblood tumors
what percentage of people with prostate cancer have the TMPRSS2/ERG gene fusion
50%
= from a translocation
what has allowed the detection of chromosmal translocations in solid tumors
New sequencing techniques
- illumina
= discovered chromosomal translocations happen at massively different frequencies in various solid tiumors for unkonw reasons
what is chromthripsis
“localised firestorms” of chromosomes
single chromosome or region undergoes massive fragmentation and stitched back together in a weird way
= numerous rearrangements (deletions, inversions, duplications) concentrated in a small genomic area
= unlike the gradual accumulation of mutations seen in most cancers
what percetage of bone cancers does Chromothripsis occor in
25%
= 3% of all cancers overall
using throid cancer as an example describe chromothripsis
catastophic chromsome breakage due to ‘unkown mechanism’
cluster of 77 translocations on short arm of chromosome 9
= after localised ‘shattering’ of DNA = re-joining of fragments to produce MASS chromsomal rearrangements
define a solid tumor
abnormal mass of tissue that forms when cells grow and divide uncontrollably, creating a distinct lump or structure
what are the 3 defects that occor in solid tumors
Mis-segrefgation of chromosomes
Genetic instability syndromes
Inherited breast cancer
what are the main caises of aneuploidy
Mis-segregation of chromosomes during mitosis
describe the normal/amphitellic segregation of chromosomes and the monotelic version causing anneploidy
chromosomes line up on equator of cells and mitotic spindle fibres/microtubules attach to kinetichores
= chromatids pulled apart towards centrosome at poles of cells
Monotelic:
failure to seperate chromatids –> one cell receives both copies
what is the nake of the checkpoint that ensures chromatids seperated correctly
M-phase checkpoiny
what is it called when a daughter cells receieves an extra chromosme due to both chromatids going to same pole
Non-disjunction
= failure of chromatids to seperate
cause of Non-disjunction
Chromatids fail to seperate
Incorrect centrome/kinetichore attachment to spindle microtubules
what monitors correct spindle assembly normally
Spindle assembly checkpoint - SAC
decsribe how the SAC monitors correct spindle assembly
- SAC senses improperly/unattached kinetochores
- recruit SAC proteins to form Mitotic Checkpoint Complex (MCC) –>includes CDC20
- MCC binds and inhibits the Anaphase-Promoting Complex (APC)
= APC triggers anaphase by degrading securin and cyclin B
= Releases separase –> cuts cohesin holding sister chromatids
= Inactivates CDK1 = exit cell cell cycle
SAC activation = APC inhibition = cell cycle arrest in metaphase
describe what normally happens when Anaphase-promoting complex is activated
degrades securin and cyclin B
- securin bound to seperase –> released seperase cuts cohesin between chromatids
- Cyclin B bound to CDK1 –> cyclin B destruction inactivates CDK1 –> exits cell cycle/move into telophase
= Persistence of CDK1-cyclin B would prevent mitotic exit, trapping the cell in metaphase
define chromosomal instability (CIN)
increased rate of changes in chromosome structure and number during cell division
= leading to aneuploidy
what percentage of soliud tumoprs exhibit chromosome instability - CIN
85%
result of anneuploidy in cancer
CIN cells gain/lose chromsomes as they divide –> different sub-populations of cancer cells with different chromosme number
= aneuploidy contribution of cancer/tumorgenisis is only partly understood
name 3 genetic instability syndromes that affect DNA repair
Ataxia telangiectasia - ATM gene
Blooms syndronme - DNA helicase
Fanconis anaemia - multiple genes involved
what is blooms syndrome
autosomal recessive disorder caused by mutations in the BLM gene
= codes a DNA helicase leading to genomic instability
Elevated Sister Chromatid Exchanges due to crossover products in HR
= Demonstrates how DNA repair failures drive chromosomal chaos.
charecteristic of blooms syndrome and why
Elevated sister chromatid exchange
BLM gene codes for helicase that usaully = Suppresses illegitimate recombination between sister chromatids
mutation –> excessive HR between chromatids
