Genomic Instability Flashcards
Genomic Instability
Changes in a cell’s DNA that make additional changes more likely. ex: gatekeeper mutation
Mutagen/Carcinogen starts neoplasia by creating a mutation that is not fatal to the cell but instead give the cell a(n) ________.
advantage
Features of Neoplasia: Uncontrolled replication
- Growth in response to new signals, or autonomously (ONCOGENES)
- Loss of usual checks on growth (LOSS OF TUMOR SUPPRESSORS). Including loss of contact inhibition
Features of Neoplasia: Immortality
- Disruption of apoptosis
- Activation of telomerase
Features of Neoplasia: Loss of DNA repair
Gatekeeper mutations
There is good evidence that the metastatic sub-clone changes to become more like a __________ cell.
mesenchymal
Neoplasia starts strictly monoclonal or polyclonal?
monoclonal
By implication, then, benign tumors are those which acquire features of a neoplasm, but the level of genomic instability is ______________.
markedly less
True or False? Treatment Implications from Genomic Instability: The Different Subclones May Respond to TOTALLY Different Chemotherapy Regimens!
True
-ex: KRAS gene
Most chemotherapeutics ________ mutations
INCREASE (remember more ways down the pyramid than up)
Targeted chemotherapy can…
reduce the chance of additional mutation
Ex: CML –> Lowers rate of replication, and slows additional genomic instability
Macro genomic instability:
Chromosomal instability
Micro genomic instability:
Nucleotide instability
Alterations that make changes at the level of chromosomes more likely
macro genomic instability
examples of macro instability
Translocations, deletions, inversions of chromosomes
Alterations that make changes in individual nucleotides (within gene level changes) more likely
micro instablilty
examples of micro instability
- Increased point mutations
- small deletions
- insertions
Mechanisms of macro level instability
Mutations in genes involved in centrosome and telomere stability, loss of cell cycle checkpoints, sister chromatid cohesion and chromosome segregation, centrosome duplication, double strand break repair (hypomethylated DNA more unstable)
t(14;18) = a chromosome change that is diagnostic of what?
follicular lymphoma
t(X,18) = a chromosome change that is diagnostic of what?
synovial sarcoma
Translocations
Fuse new and interesting oncogenes (Bcr-abl)!
Deletions
Wipe out that annoying tumor suppressor!
Inversions
Wrong gene in the wrong place? Two wrongs make the right way to tumor!
Mechanism of micro level instability: point mutations and deletions are a very common way to remove what cell cycle tumor suppressor?
p53
