Oncogenes Flashcards
What are the 2 basic pathways that drive genetic changes in cancers?
1) Chromosomal instability
2) Microsatellite instability
What is hayflick’s limit?
The concept that normal cells have a limited lifespan
Malignant cells are immortal b/c they avoid ______
Hayflick’s limit
How does shortening of telomeres contribute to chromosomal instability?
When telomeres shorten and reach hayflick’s limit, every round of DNA replication results in double stranded DNA breaks. This leads to catastrophic genome wide rearrangements. Most of these cells will die but some are able to rearrange in a manner that results in survival due to reactivation of telomerase. However, these cells contain a massive amount of genetic rearrangements that are highly likely to result in cancer upon further divisions.
Describe how mistakes in mitosis can lead to aneuploidy (incorrect # chromosomes in cell).
Microtububles attach incorrectly to chromosomes during mitosis. Microtubules are supposed to attached to single kinetochore. However, sometimes a microtubule can fail to attach (monotelic), or microtubules from one pole can attach to both kinetochores of the same chromosome (syntelic), or microtubules from both poles can attach to the same chromosome (merotelic).
Microsatellite instability is associated with what DNA repair mechanism?
Mismatch repair
What is microsatellite instability?
Discrete areas with a lot of point mutations that are simple sequence repeats in the genome
What is the Philadelphia Chromosome?
Robertsonian reciprocal translocation between chromosome 9 at the ABL gene and chromosome 22 at the BCR gene that results in constitutively active tyrosine kinase due to fusion protein (BCR-ABL)
Chronic Phase of CML
- What cell type is overproduced in this phase?
- Are cells able to differentiate in this phase?
- Granulocytes
- Yes
Blast Crisis Phase of CML
- What causes progression to this stage?
- What occurs in this phase that results in cancer?
- How does differentiation potential change in this phase?
- Additional rearragements of the genome (new mutations)
- Loss of tumor suppressors (p53, pRb, etc.)
- Additional mutations that lead to less differentiated highly proliferative cells and more aggressive disease
How does imatinib treat CML?
It inhibits the activity of the ABL kinase, so it reduces the activity of the fusion protein. The cancer cells are so dependent on the activity of this fusion protein that blocking its activity results in apoptosis of BCR-ABL positive cells.
What is oncogene addiction?
Refers to the fact that cancer cells become reliant upon a limited number of growth pathways. This may arise due to a limited number of driver mutations that interact with genomic instability. It is also possible that darwinian selection maintains these driver muations and other survival pathways are lost. As such, disruption of these addicted pathways can result in diminished cancer potential.
Epstein Barr virus is associated with _________
Burkitt Lymphoma
Burkitt Lymphoma is associated with translocation involving what gene?
myc gene on chromosome 8 is fused to the heavy chain immunoglobin locus on chromosome 14
