L05 - Oncogenes Flashcards
What is a proto-oncogene?
A normal regulatory gene, that promotes normal cell growth & proliferation in a regulated manner, encoding proteins involved in signal transduction that can be mutated to become an oncogene
What is an oncogene?
A mutated form of the corresponding proto-oncogene that induces abnormal cell proliferation and tumour development
In what 4 ways can a proto-oncogene gain a function mutation to become an oncogene?
1 - Point mutation
2 - Amplification of a DNA segment that includes a proto-oncogene
3 - Chromosome translocation that brings a growth regulatory gene under the control of a different promoter
4 - Chromosome translocation that joins two genes together, creating a fusion gene
Give two examples of proto-oncogenes that gain their function mutations by point mutation.
1 - Ras
2 - EGFR
Give two examples of proto-oncogenes that gain their function mutations by amplification.
1 - MYCN
2 - EGFR
Give two examples of proto-oncogenes that gain their function mutations by chromosome translocations that bring a growth regulatory gene under the control of a different promoter.
1 - c-MYC
2 - BCL-2
Give an example of a proto-oncogene that gains its function mutation by chromosome translocations that join two genes together, creating a fusion gene.
- BCR & ABL
What are the 3 members of the RAS oncogene family?
1 - KRas
2 - NRas
3 - HRas
Which 3 codons on Ras genes do oncogenic point/missense mutations invariably involve?
1 - G12
2 - G13
3 - Q61
*G = glycine and Q = glutamine
How do G12, G13 and Q61 point mutations produce oncogenic activity in Ras?
They make Ras unresponsive to GAP activity, which is necessary to deactivate Ras by converting the GTP on Ras to GDP
In which area of the Ras protein are the products of the G12, G13 and Q61 genes?
The nucleotide-binding pocket (where GTP binds)
How many alleles of a proto-oncogene must be mutated in order to create oncogenic activity of that particular gene?
Only one
Which mutations in EGFR also cause increased activity of Ras?
- In frame deletions aa 747-752: these change the protein conformation, which prolongs the active dimer configuration
- Missense mutation L858R (leu > arg): this increases kinase activity 50-fold
Which cancers are caused by amplification of which genes?
- MYCN - Neuroblastoma
- c-MYC - Small cell lung cancer, Breast cancer, Ovarian cancer, Oesophageal cancer
- Cyclin D1 - Breast cancer, Oesophageal cancer
- EGFR - Glioblastoma
What are double minutes?
Of which gene are they a common feature?
- Small fragments of extrachromosomal DNA as a result of gene amplification
- They are a common feature of the MYCN gene
What are homogeneously staining regions?
Of which gene are they a common feature?
- Multiple copies of a gene on the same chromosome as a result of gene amplification
- They are a common feature of the MYCN gene
What is MYCN amplification associated with?
Aggressive disease, metastatic potential, therapeutic resistance and poor patient outcomes
What is MYC?
How does it work?
- MYC is a transcription factor, and MYC proteins compete with MAD for binding MAX
1 - MYC/MAX – activation of gene expression
2 - MAD/MAX – repression
- ∴ if MYC > MAD, MYC outcompetes MAD for MAX, leading to increased expression
- MYC binds promoters of a large proportion of genes already active in the cell; wide activation leads to a generally more aggressive cancer
- It significantly increases the expression of these actively transcribed genes
What is a hallmark of Burkitt lymphoma?
Translocations involving c-MYC
What chromosomal translocation do all Burkitt lymphoma tumour cells carry?
- All BL tumour cells carry a chromosomal translocation involving c-MYC gene on chromosome 8 and one of the immunoglobulin gene loci:
1 - t(8;14) MYC – IgH (85%)
2 - t(2;8) MYC – IgK
3 - t(8;22) MYC – IgL
What is the outcome of the MYC / IgH translocation?
- The translocation places the IgH enhancer adjacent to c-MYC
- Since IgH is highly expressed by the IgH enhancer to produce antibodies, the translocation causes the IgH enhancer to powerfully up regulate c-MYC
- c-MYC binds with MAX to E-box sequences
- Genes required for cell growth, proliferation, ribosomal & protein synthesis, metabolism, & energy generation are unregulated (i.e. the hallmarks of cancer)
What chromosomal translocation occurs in follicular lymphoma?
- BCL12-IgH translocation
- BCL12 is a pro-survival gene
Which chromosomal translocation is a hallmark of chronic myeloid leukaemia?
- BCR-ABL
- Philadelphia chromosome
t(9;22)-(q34;q11)
What is oncogene addiction?
- A process in which cancers with genetic, epigenetic, or chromosomal irregularities become dependent on one or several genes for maintenance and survival
- As a result, cancer cells rely on continuous signalling from these oncogenes for their survival
- Growth and survival can be significantly impaired by the inactivation of a single driver mutation
What is the treatment for cancers caused by oncogene addiction?
Targeted therapy - tyrosine kinase inhibitors (TKIs)
Describe 1st generation TKIs.
- e.g. gefitinib, erlotinib
- Competitive ATP-mimics with reversible binding
- Frequent drug resistance e.g. T790M (as the ATP out-competes the inhibitor)
Describe 2nd generation TKIs.
- e.g. Afatinib, Dacomitinib
- Irreversible binding in the ATP pocket
Describe 3rd generation TKIs.
- e.g. osimertinib
- Bind more avidly to EGFR T790M mutants than wild-type EGFR
