3rd Feb - Aneuploidy, CIN and Mitotic errors Flashcards
What is aneuploidy?
The presence of an abnormal number of chromosomes in the cell
How can aneuploidy be detected?
By FISH on the whole karyotype
What is the most common genetic change associated with cancer?
Aneuploidy present in >90% of cancers
Give an example of a common aneuploidy in cancer
Chr 3 in melanomas
Chr 7 in renal carcinomas
What is CIN?
Chromosome instability - a type of genomic instability in which chromosomes are unstable such that whole or parts of chromosomes are duplicated/deleted, over generations
What does CIN cause?
Different cells within the tumour have quite different sets of chromosomes
What are the two different forms of CIN?
Numerical
Structural
What causes numerical CIN?
Results from errors in chromosome segregation during mitosis such as:
- Defective chromosome cohesion
- Centrosome amplification
- Merotelic chromosome attachments
- Mitotic checkpoint defects
- Cell division failure
What causes structural CIN?
Could result from mitotic errors or pre-mitotic errors such as replication stress
How are sister chromatids held together?
They must be held together from S phase to anaphase
They are held together by cohesion complexes: SCC1, SCC3, SMC1 and SMC3 which form a ring around the sister chromatids. They are loaded onto chromsomes at the beginning of the cell cycle.
Outline common mutations causing loss of sister chromatid cohesion
Mutations in cohesin are common in colorectal cancer
Inactivating mutations in SCC3 cause premature loss of cohesion
How do cancer cells acquire multiple centrosomes?
Uncoupling of centrosome duplication from the cell cycle
Failure of cells to divide during mitosis
How have cancer cells adapted to prevent cell death from chromosome missegregation caused by centrosome amplification?
Centrosome clustering causes multiple centrosomes to cluster creating pseudo-bipolar mitosis
Outline the process of kinetochore attachment in a functional cell
- Unattached chromosome at pro-metaphase
- 1 kinetochore binds laterally to a control MT
- Chromosome slides towards the spindle pole
- Lateral attachment inverts to an end-on unipolar attachment, microtubule now called kinetochore MT
- Free kinetochore captures microtubules from opposite spindle pole to convert unipolar to bipolar attachment
What is a syntelic chromosome attachment?
Some centrosomes attach to kinetochores on both sister chromatids