Graeme Finlay-1 Flashcards
What occurred following the Chernobyl accident?
There was an increase in the frequency of papillary thyroid cancer in the Ukraine increased 10-30 fold
What is papillary thyroid cancer?
This is a radiation-associated cancer which affects mainly children, the radiation induced form is more aggressive than the sporadic from
Activates the proto-oncogene RET through chromosomal rearrangements that fuse it with other genes (60-70% of radiation induced cancers and on 5-30% of sporadic ones)
They also contain RET rearrangements at the earliest stages of development
How does the proto-oncogene RET become activated?
This can undergo fusion with at least 12 other genes
One of these is the H4 gene which is found 30Mb way on the same chromosome
Why are H4 and RET so frequently rearranged?
The distance between RET and an irrelevant linked marker showed a distance compatible random folding of a flexible linear polymer (a Rayleigh distribution)
The distance between RET and H4 showed a markedly non-random distribution the two genes were position very close to each other more frequently than would be expected from a Rayleigh distribution
Loops of DNA extend into channels between domains in the nucleus in a way that is related to cellular differentiation, specific loops are juxtaposed and breaks induced by a track of radiation produce free ends in close proximity, during repair the wrong ends are joined
What is RET?
This gene encodes a tyrosine kinase growth factor receptor
What is typical of the fusion RET protein?
The fusion RET protein shows altered levels of expression (as it comes under control of the H4 promoter etc) Localises abnormally in the cytoplasm (due to loss of the transmembrane domains) Constitutively dimerises (due to oligomerisation domains) resulting in auto phoshphorylation and signals to Cgamma, IRS-1, Shc and Grb2
What are telomeres?
These are repeated sequences (TTAGGG) that cap the ends of chromosomes and maintain chromosome stability
They maintain their length during embryogenesis by an enzyme called telomerase
How do mice and humans differ in the biology of their telomeres?
Adult mouse tissues express telomerase, have long telomeres and (when carrying a mutant TSG) develop sarcomas and lymphomas
Adult human tissues however repress telomerase, have short telomeres and develop predominately carcinomas, the telomeres become shorter each time a cell divides, this causes human cells to undergo a limited number of divisions before coming senescent
the erosion of telomeres contributes to genetic instability seen early in cancer
What occurs to telomeres in transgenic mice with a disrupted telomerase RNA component and p53 genes?
At generations 0-2 when the telomeres of the mice were still long the mice tended to produce sarcomas and lymphomas as would commonly be seen in wild type mice
At generation 5 and beyond when the telomeres were greatly shortened the mice generated many carcinomas which is more typical of a human phenotype with marked aneuploidy and fusions/translocations
This shows how loss of telomeres facilitates carcinogenesis, especially of epithelial cells and induction of telomerase is required for cancer maintenance
What is the BFB cycle?
This is where telomeres shorten during excessive cell proliferation in premalignant stages of tumour growth
A lack of telomere function leads to telomeric fusions and dicentric chromosomes which initiate the breakage-fusion-bridge cycle where
Lagging chromosomes and anaphase bridges are generated during mitosis
Chromosome breakage releases recombinogenic free DNA ends which can invade other chromosomes and generate non-reciprocal translocations
Cancer induction follows the generation of deregulated or chimeric oncogenes at breakpoints or altered gene dosage
Non-reciprocal translocation are characteristic of carcinomas while reciprocal translocations are characteristics of paediatric cancers
In human breast carcinoma the acquisition of genetic instability occurs following the telomere crisis as ducts progress from hyperplasia to ductal carcinoma in situ
What can cause aneuploidy?
Aneuploidy can arise from defects in kinetochorr-microtubule attachments and from supernumeracy centrosomes which are often observed in cancer cells
What is merotely?
Merotely is when microtubules from both poles attach to the kinetochore of one chromatid the resulting gain or loss of a chromosome may provide variation upon which selection acts to drive tumour evolution
What are lagging chromosomes?
These are located in micronuclei, during S phase some DNA repair is detected in both the nucleus and the micronuclei in G2 phase, DNA repair resolves in the nucleus but continue at high levels in the micronucleus as shown by gammaH2AX which is a phosphorylated histone marker that marks areas of DNA repair
The TUNEL assay which identifies cells with broken, single stranded DNA
What do the markers showing high levels of DNA repair in the micronucleus mean?
It indicates that the micronucleus undergoes replicative stress
DNA synthesis is delayed relative to the nucleus
There is a decrease in components of the DNA damage response such as p53BP1
Micronucleus may have less efficient uptake mechanism for proteins this leads to replicative stress, chromosome pulverization and repair o give highly rearranged chromosomes or chromothripsis
