Oncogenes

Question 1

What are the 2 basic pathways that drive genetic changes in cancers?

Answer 1

1) Chromosomal instability
2) Microsatellite instability

Question 2

What is hayflick’s limit?

Answer 2

The concept that normal cells have a limited lifespan

Question 3

Malignant cells are immortal b/c they avoid ______

Answer 3

Hayflick’s limit

Question 4

How does shortening of telomeres contribute to chromosomal instability?

Answer 4

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.

Question 5

Describe how mistakes in mitosis can lead to aneuploidy (incorrect # chromosomes in cell).

Answer 5

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).

Question 6

Microsatellite instability is associated with what DNA repair mechanism?

Answer 6

Mismatch repair

Question 7

What is microsatellite instability?

Answer 7

Discrete areas with a lot of point mutations that are simple sequence repeats in the genome

Question 8

What is the Philadelphia Chromosome?

Answer 8

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)

Question 9

Chronic Phase of CML

• What cell type is overproduced in this phase?
• Are cells able to differentiate in this phase?

Answer 9

• Granulocytes
• Yes

Question 10

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?

Answer 10

• 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

Question 11

How does imatinib treat CML?

Answer 11

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.

Question 12

What is oncogene addiction?

Answer 12

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.

Question 14

Epstein Barr virus is associated with _________

Answer 14

Burkitt Lymphoma

Question 15

Burkitt Lymphoma is associated with translocation involving what gene?

Answer 15

myc gene on chromosome 8 is fused to the heavy chain immunoglobin locus on chromosome 14

Question 16

Mantle cell lymphoma targets the _____ gene

Answer 16

Cyclin D

translocation between cyclin D locus on chromo 11 and Ig heavy chain gene enhancer region on chromo 14

Question 17

What translocation leads to follicular lymphoma (B-cell Lymphoma 2)

Answer 17

Places Ig heavy chain gene enhancer (chromo 14) into BLC2 locus on chromosome 18

Question 18

What are 2 ways in which DNA can be amplified?

What can DNA amplification result in at the cellular level?

Answer 18

• Individual segments of a chromosome can be amplified (expanded in size)
• Double minute portions of DNA (aberrant portions of DNA that are not a chromosome, but rather extra portions of DNA in the nucleus)
• Overexpression

Question 19

If overexpression is observed, is DNA amplification always also present?

Answer 19

No - over expression can occur with normal amount of genomic information, could be due to aberrant promoter activity / RNAPol activity

Question 20

What type of mutation occurs in Ras and Raf (MAPKKK) protein that alters the Ras signaling pathway?

Answer 20

• Ras: Point mutations that cluster at specific codons keep Ras in the GTP bound sate –> constitutively active –> constant stimuli that promote cell proliferation (MAPK)
• Raf: point mutations that cluster at specific codons alter the acivity of Raf and can lead to activation of oncogenes through MAPK pathway that promotes cell proliferation