13. Chromosomes and cancer 2 Flashcards
What are solid tumours?
Tumours formed in solid organs like CRC or ovarian cancer
What are the characteristics of solid tumours?
- Need around 6-8 events for a tumour to become malignant. (unlike blood cancers)
- Highly aneuploid due to abnormal chromosomal segregation.
- deletions are important especially in the loss of tumour suppressor genes
What are some common deletions in tumours?
- del(13)(q14) of Rb and retinoblastoma
- del(17)(q11.2) of NF1 and neuroblastoma
- del(11)(p13) of WT1 and wilms tumour
What is the variability of chromosomal aberrations in solid tumours?
- Considerable variability to which tumour genomes are aberrant
- there is a big range of chromosome differences in different tumours
- This variability makes it hard to work out the cause/driving mutations of the cancer and what are cytogenetic noise.
Why can some mutations have knock on effects?
- Pathways like tyrosine kinase signalling can trigger many signalling cascades and have many effects
- Some genes in the pathway can be unregulated and some are downregulated
- some genes have separate effects
- some genes have additive effects and create a more aggressive cancer phenotype
How is our understanding of chromosome aberrations changing?
- Translocations were originally thought to be present uniquely in haematopoietic tumours
- The use of NGS techniques are detected translocations in solid tumours
- The 1st solid tumour translocation is involved in androgen and serine proteases and transcription factors
- This translocation leads to gene fusion [TMPRSS2/ERG] which is present in 50% of prostate cancers
Why is understanding chromosomal aberrations important?
we can use to inform and develop new treatments
What did the use of NGS in solid tumours find?
That chromosomal translocations occur at massively differing frequencies in various solid tumours for unknown reasons.
What are Circos plots?
- A graphic way of depicting chromosomal translocations.
- Purple lines show where material has moved from 1 chromosome to another
- green lines show where there are translocations and amplifications with 1 chromosome
What is Chromothripsis?
a localised firestorm of chromosomal rearrangements
What causes Chromothripsis?
An event that shatters a limited stretch of the genome which is then not repaired correctly resulting in random arrangements of the fragments. We do not know the mutational mechanism behind this.
What cancers is Chromothripsis normally found in?
- 25% of bone cancers
- 2-3% of all cancers
What kind of mutations are involved in Chromothripsis?
- tail to tail inversions
- head to tail inversion
- deletions
- some info is lost to the cell completely
How does the karyotype of cancer cells change by altering chromosomal number?
- change in chromosome number without changing their structure
- this creates aneuploidy
- aneuploidy leads to chromosomal instability in around 85% of sporadic carcinomas
What does chromosomal instability do in cancer?
- it contributes to the general chaos that progressively envelops the cancer cells as they advance to high malignancy
- used by tumours to scramble their genomes to arrive at chromosome arrangements which are more favourable neoplastic growth
Can aneuploidy vary in the same tumour?
Yes
some cells can have the normal 2 copies whereas others have upwards of 11 copies
What can aneuploidy lead to?
- dysregulated signalling
- abnormal cell growth
- altered apoptosis
- amplification
What are the changes in chromosome number caused by?
Mis-segregation of chromosomes during mitosis
How long does chromosomal segregation take?
30 mins due to evolutionary optimisation
What is responsible for separating the chromosomes?
the mitotic spindle complex
How many cells in your body divide in 1 day?
1/2 trillion
What is the error rate in normal cell division?
0.5-5 per 100 cell divisions but most are repaired or detected
What is the error rate in cancer cell division?
25 in 100 divisions will introduce a new mutation
What makes up a mitotic spindle?
- 2 centromeres
- microtubules that attach to the kinetochores
Why is more then 2 centromeres bad?
it leads to mis segregation of chromosomes and tri/quad radial chromosomes
How can you get aneuploidy?
- monotelic attachment
- syntelic attachment
- merotelic attachment
What is monotonic attachment?
Only 1 kinetochore is caught by the microtubules so an unequal force is applied to the chromosome so both chromatids are pulled to one pole.
What is syntelic attachment?
1 spindle attaches to both kinetochores so an unequal force is applied and both chromatids are pulled to 1 pole
What is merotelic attachment?
1 microtubule attaches to both kinetochores and the other attaches to 1 kinetochore and there is an unequal force.
Unpredictable results and it probably won’t be detected due to both kinetochores being attached.
What does the SAC checkpoint detect?
Unattached kinetochores
How can squashing a cell lead to aneuploidy?
- This squashing can mess around and put mechanical pressure on the mitotic spindle and incorrect segregation.
- This usually happens when cancer cell metastasise and force themselves through membranes
- The smaller the gap, the more stress and the more mis segregation
What detects the mis-segregation in M phase?
M phase checkpoint complex
What is non-disjunction?
when both chromatids go to one pole so the daughter cell will have an extra chromosome
What is a result of non disjunction?
the other cell will not have a chromosome and the information will be lost
Why is it important to ensure kinetochores are attached correctly?
to prevent aneuploidy
Why is have only 2 centromeres important?
- to make a bipolar spindle so the chromosomes separate into the 2 daughter cells
- multipolar spindles lead to chaos in pulling the chromosomes apart
What is the SAC?
Spindle assembly checkpoint
What is the structure of the kinetochore?
- the landing pad where the microtubules attach
- A complex of kinases at the landing pad to initiate signalling
What happens at SAC when the kinetochores are not attached?
- Mad2 is present as C-Mad2
- C-Mad2 interacts with CDC20 and forms the mitotic checkpoint complex (MCC).
- As CDC20 is in the MCC it cannot bind the anaphase promoting complex
- C-Mad2 also acts as a cytoplasmic signal to tell the cell the kinetochores are not attached
- Mitosis stalls
What are the 2 forms of Mad2?
- O-Mad2 = open Mad2
- C-Mad2 = closed Mad2
What happens at the SAC when all the kinetochore are attached?
- C-Mad2 is not made and it exists as O-Mad2
- C-Mad2 doesn’t bind CDC20 and doesn’t form the MCC
- CDC20 attaches to the anaphase promoting complex
- mitosis continues
How are the chromosomes separated once it has passed the SAC?
- APC ubiquitinates some molecules to flag them for degradation
- This includes securin
- ubiquitinated securin separates from separase
- Separase cuts the protein cohesin that joins the chromosomes together
- This means the chromosomes can separate
How can SAC be silenced and what can this lead to?
- Mutation, methylation or over expression
- all can prevent MCC control
What are the effects of aneuploidy in cancer?
- chromosome instability
- gain or loss of chromosomes
- more = metastasis, resistance to treatment, disease progression
- not understood its contribution to tumourigenesis
What causes genetic instability syndromes?
defects in DNA repair that leads to increased cancer risk
Bloom’s syndrome
- Early onset cancer
- diagnosis based on the appearance of chromosomes during cell division
- produces a harlequin pattern that shows lots of exchange of genetic material
What can mutations lead to?
increased chromosomal instability which leads to increased chance of accumulating genetics changes that will lead to cancer
What are BRCA1/2?
- associated with cellular response to DNA damage
- mutation is associated with major chromosomal changes
- BRCA1/2 are structurally and functionally different
- They are encoded on different chromosomes
What DNA repair is BRCA1/2 involved in?
Homologous recombination
What happens in BRCA1/2 mutation?
HR repair falls apart and causes chromosomal changes including triradial chromosomes
