Oncogenes Flashcards
Define proto-oncogene.
A normal regulatory gene encoding proteins involved in signal transduction that can be mutated to become an oncogene.
Define oncogene.
A mutated form of the corresponding proto-oncogene that induces abnormal cell proliferation and tumour development.
List 4 ways by which a proto-oncogene can 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 an example of a proto-oncogene that gains its function mutation by point mutation.
Ras.
List 5 proto-oncogenes that gain their function mutations by amplification.
1 - MYC.
2 - MYCN.
3 - MYCL.
4 - HER.
5 - CCND1.
Give an example of a proto-oncogene that gains its function mutation by chromosome translocations that bring a growth regulatory gene under the control of a different prometor.
MYC.
List 2 proto-oncogenes that gain their function mutations by chromosome translocations that join two genes together, creating a fusion gene.
1 - BCR and ABL.
2 - PML and RARA.
List the 3 members of the RAS oncogene family.
1 - KRAS.
2 - NRAS.
3 - HRAS.
In what proportion of cancers are RAS function mutations present?
25%.
Give an example of a cancer for which HRAS is the most common oncogene.
Head and neck squamous cell carcinoma.
Give an example of a cancer for which NRAS is the most common oncogene.
Melanoma.
Give an example of a cancer for which both NRAS and KRAS are the most common oncogene.
Multiple myeloma.
List 3 cancers for which KRAS is the most common oncogene.
1 - Pancreatic ductal adenocarcinoma.
2 - Colorectal adenocarcinoma.
3 - Lung adenocarcinoma.
Which ras oncogenes are involved in acute myeloid leukaemia?
All 3 members (K, N and HRAS).
List the 3 most common sites for point mutations on RAS genes.
1 - G12.
2 - G13.
3 - Q61.
*G = glycine and Q = glutamine.
Which site of mutation is most common in KRAS?
G12.
Which site of mutation is most common in NRAS?
Q61.
Which site of mutation is most common in HRAS?
All 3 of the most common sites are affected to an equal degree.
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 chromosomes of a proto-oncogene must be mutated in order to create oncogenic activity of that particular gene?
Only one.
Give an example of a cancer caused by amplification of the MYCN gene.
Neuroblastoma.
List 4 cancers caused by amplification of the MYC gene.
1 - Breast cancer.
2 - Oesophageal cancer.
3 - Ovarian cancer.
4 - Small cell lung cancer.
List 2 cancers caused by amplification of the CCND1 gene.
1 - Breast cancer.
2 - Oesophageal cancer.
List 2 cancers caused by amplification of the HER gene.
1 - Breast cancer.
2 - Glioblastoma.
What are double minutes?
Of which gene are they a common feature?
- Autonomously replicating extrachromosomal fragments of DNA.
- They are common with MYCN amplification.
What are homogeneously staining regions?
Of which gene are they a common feature?
- Autonomously replicating strands of DNA that grow attached to the end of a chromosome.
- They are common with MYCN amplification.
What is MYC?
How does it work?
- A transcription factor that controls:
1 - The cell cycle.
2 - Metabolism.
3 - Differentiation.
4 - Angiogenesis.
- When bound to MAX, the MYC-MAX complex acts as a co-activator complex at E-box elements (a type of gene promoter).
How does the activity of the MAX transcription factor differ when bound to transcription factors other than MYC?
- When MAX is bound to MAD1, they act as co-repressors.
- MYC-MAX and MAX-MAD1 have antagonistic effects.
How does MYC differ from most other transcription factors?
MYC is more non-specific than most other transcription factors, and can increase expression of many genes.
What type of translocation occurs between MYC and IgH?
Between which chromosomes does the translocation occur?
On which chromosomes are MYC and IgH found?
- Reciprocal translocation.
- Between chromosome 8 (MYC) and 14 (IgH).
What is the outcome of the MYC / IgH translocation?
- MYC comes into the control of the promoters of the IgH gene, leading to overexpression in cells that normally produce immunoglobulin heavy chains in high quantities.
- This means that the MYC / IgH translocation commonly affects B cells, so gives rise to Burkitt lymphoma.
Give an example of a pair of genes (other than BCR and ABL) that gain their function mutation by translocation to form a fusion gene.
Give the full names for each gene.
1 - PML - promyelocytic leukaemia protein.
2 - RARA - retinoic acid receptor alpha.
Which cancer is caused by the PML-RARA fusion gene?
Acute promyelocytic leukaemia.
What is the function of the protein product of RARA?
What must happen in order for it to function?
- It is a transcription factor.
- It only activates transcription when bound to a ligand.
What is the protein product of PML?
List the functions of PML.
- It is the core component of nuclear structures known as PML nuclear bodies. These bodies are involved in:
1 - Mediating interactions between proteins.
2 - Post-translational modification of proteins.
3 - Cell cycle regulation.
4 - Enhancement of p53 stability, a tumour suppressor gene that promotes apoptosis.
How does the PML-RARA fusion gene produce this oncogenic activity in haemopoietic stem cells?
- The PML-RARA fusion gene ceases differentiation at the promyelocyte phase of the myeloid lineage.
- It does this by producing a disorganised PML nuclear body in the nucleus mixed with the RARA transcription factor (formation of a dimer).
Direct effect:
- Disruption of PML nuclear bodies disrupts normal cellular function via loss of regulation (e.g. loss of p53, reducing apoptosis).
Indirect effect:
- The dimer also attracts corepressors which target repress the target genes for RARA. These genes are important for myeloid differentiation.
List 2 treatments for acute promyelocytic leukaemia.
How do they work?
1 - Arsenic trioxide, which degrades the PML/RARA dimer.
2 - Retinoic acid, which converts corepressors attracted by the PML/RARA dimer into activators.
Define oncogene addiction.
Which type of oncogenes are usually involved in oncogene addiction?
List 4 specific oncogenes of this type and give an example of a cancer caused by each gene.
- The phenomenon where a tumor cell, despite the presence of multiple genetic alterations, can exhibit dependence on a single oncogenic pathway or protein for its sustained proliferation and/or survival.
- These are usually oncogenes encoding tyrosine kinase domains:
1 - BCR-ABL: chronic myeloid leukaemia.
2 - HER: non-small cell lung cancer (NSCLC).
3 - ALK: non-small cell lung cancer & neuroblastoma.
4 - MET: lung, liver, head & neck cancers.
What is the treatment for cancers caused by oncogene addiction?
Tyrosine kinase inhibitors.
List 2 mutations that are most common with the HER gene.
1 - Missense substitution.
2 - Inframe deletion.
What is the outcome of all mutations to HER genes?
Increased activation of EGFR.
Give an example of a cancer that arises from missense mutations in the kinase domain of HER genes.
Non-small cell lung cancer.
Give an example of a cancer that arises from small inframe deletions / insertions in the kinase domain of HER genes.
Non-small cell lung cancer.
Give an example of a cancer that arises from large deletion mutations in the kinase domain of HER genes.
Glioblastoma.
List the cancers that arise from amplification of HER genes.
1 - Non-small cell lung cancer.
2 - Glioblastoma.
3 - Colorectal cancer.
Why do patients often relapse with tyrosine kinase inhibitor therapy?
Because secondary mutations arise that affect the target site of the drugs.
Which amino acids of the HER genes are most commonly affected by inframe deletions?
Amino acids 747-752.
List the 2 most common changes to HER genes that occur with missense mutations.
What effect do these changes have on the EGFR protein?
What is the clinical outcome?
1 - A change from leucine to arginine.
- This increases kinase activity 50-fold, resulting in non-small cell lung cancer.
2 - A change from threonine to methionine.
- This changes the ATP binding socket, causing drug resistance.
List 4 treatments for EGFR oncogene addiction in non-small cell lung cancer.
- First generation tyrosine kinase inhibitors are reversible (competitive) ATP mimics:
1 - Gefitinib.
2 - Erlotinib.
Second generation tyrosine kinase inhibitors are irreversible (non-competitive) ATP mimics:
3 - Afatinib.
Third generation tyrosine kinase inhibitors are more avid binders of EGFR mutants compared to the EGFR wild-type:
4 - Osimertinib.
What is a problem with second generation tyrosine kinase inhibitors?
They are relatively toxic.
Which amino acids of the HER genes are most commonly affected in glioblastomas?
Amino acids 6-73.
What is the effect of mutations to the HER gene in glioblastomas?
- Mutation to the HER gene in glioblastomas causes loss of ligand binding and regulatory domains that are necessary for dimerisation of the EGFR.
- This enables ligand-independent signalling.
