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Oncogenes Flashcards

1
Q

Define proto-oncogene.

A

A normal regulatory gene encoding proteins involved in signal transduction that can be mutated to become an oncogene.

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2
Q

Define oncogene.

A

A mutated form of the corresponding proto-oncogene that induces abnormal cell proliferation and tumour development.

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3
Q

List 4 ways by which a proto-oncogene can gain a function mutation to become an oncogene.

A

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.

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4
Q

Give an example of a proto-oncogene that gains its function mutation by point mutation.

A

Ras.

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5
Q

List 5 proto-oncogenes that gain their function mutations by amplification.

A

1 - MYC.

2 - MYCN.

3 - MYCL.

4 - HER.

5 - CCND1.

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6
Q

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.

A

MYC.

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7
Q

List 2 proto-oncogenes that gain their function mutations by chromosome translocations that join two genes together, creating a fusion gene.

A

1 - BCR and ABL.

2 - PML and RARA.

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8
Q

List the 3 members of the RAS oncogene family.

A

1 - KRAS.

2 - NRAS.

3 - HRAS.

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9
Q

In what proportion of cancers are RAS function mutations present?

A

25%.

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10
Q

Give an example of a cancer for which HRAS is the most common oncogene.

A

Head and neck squamous cell carcinoma.

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11
Q

Give an example of a cancer for which NRAS is the most common oncogene.

A

Melanoma.

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12
Q

Give an example of a cancer for which both NRAS and KRAS are the most common oncogene.

A

Multiple myeloma.

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13
Q

List 3 cancers for which KRAS is the most common oncogene.

A

1 - Pancreatic ductal adenocarcinoma.

2 - Colorectal adenocarcinoma.

3 - Lung adenocarcinoma.

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14
Q

Which ras oncogenes are involved in acute myeloid leukaemia?

A

All 3 members (K, N and HRAS).

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15
Q

List the 3 most common sites for point mutations on RAS genes.

A

1 - G12.

2 - G13.

3 - Q61.

*G = glycine and Q = glutamine.

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16
Q

Which site of mutation is most common in KRAS?

A

G12.

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17
Q

Which site of mutation is most common in NRAS?

A

Q61.

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18
Q

Which site of mutation is most common in HRAS?

A

All 3 of the most common sites are affected to an equal degree.

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19
Q

How do G12, G13 and Q61 point mutations produce oncogenic activity in ras?

A

They make ras unresponsive to GAP activity, which is necessary to deactivate ras by converting the GTP on ras to GDP.

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20
Q

In which area of the ras protein are the products of the G12, G13 and Q61 genes?

A

The nucleotide-binding pocket (where GTP binds).

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21
Q

How many chromosomes of a proto-oncogene must be mutated in order to create oncogenic activity of that particular gene?

A

Only one.

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22
Q

Give an example of a cancer caused by amplification of the MYCN gene.

A

Neuroblastoma.

23
Q

List 4 cancers caused by amplification of the MYC gene.

A

1 - Breast cancer.

2 - Oesophageal cancer.

3 - Ovarian cancer.

4 - Small cell lung cancer.

24
Q

List 2 cancers caused by amplification of the CCND1 gene.

A

1 - Breast cancer.

2 - Oesophageal cancer.

25
Q

List 2 cancers caused by amplification of the HER gene.

A

1 - Breast cancer.

2 - Glioblastoma.

26
Q

What are double minutes?

Of which gene are they a common feature?

A
  • Autonomously replicating extrachromosomal fragments of DNA.
  • They are common with MYCN amplification.
27
Q

What are homogeneously staining regions?

Of which gene are they a common feature?

A
  • Autonomously replicating strands of DNA that grow attached to the end of a chromosome.
  • They are common with MYCN amplification.
28
Q

What is MYC?

How does it work?

A
  • 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).
29
Q

How does the activity of the MAX transcription factor differ when bound to transcription factors other than MYC?

A
  • When MAX is bound to MAD1, they act as co-repressors.

- MYC-MAX and MAX-MAD1 have antagonistic effects.

30
Q

How does MYC differ from most other transcription factors?

A

MYC is more non-specific than most other transcription factors, and can increase expression of many genes.

31
Q

What type of translocation occurs between MYC and IgH?

Between which chromosomes does the translocation occur?

On which chromosomes are MYC and IgH found?

A
  • Reciprocal translocation.

- Between chromosome 8 (MYC) and 14 (IgH).

32
Q

What is the outcome of the MYC / IgH translocation?

A
  • 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.
33
Q

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.

A

1 - PML - promyelocytic leukaemia protein.

2 - RARA - retinoic acid receptor alpha.

34
Q

Which cancer is caused by the PML-RARA fusion gene?

A

Acute promyelocytic leukaemia.

35
Q

What is the function of the protein product of RARA?

What must happen in order for it to function?

A
  • It is a transcription factor.

- It only activates transcription when bound to a ligand.

36
Q

What is the protein product of PML?

List the functions of PML.

A
  • 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.

37
Q

How does the PML-RARA fusion gene produce this oncogenic activity in haemopoietic stem cells?

A
  • 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.
38
Q

List 2 treatments for acute promyelocytic leukaemia.

How do they work?

A

1 - Arsenic trioxide, which degrades the PML/RARA dimer.

2 - Retinoic acid, which converts corepressors attracted by the PML/RARA dimer into activators.

39
Q

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.

A
  • 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.

40
Q

What is the treatment for cancers caused by oncogene addiction?

A

Tyrosine kinase inhibitors.

41
Q

List 2 mutations that are most common with the HER gene.

A

1 - Missense substitution.

2 - Inframe deletion.

42
Q

What is the outcome of all mutations to HER genes?

A

Increased activation of EGFR.

43
Q

Give an example of a cancer that arises from missense mutations in the kinase domain of HER genes.

A

Non-small cell lung cancer.

44
Q

Give an example of a cancer that arises from small inframe deletions / insertions in the kinase domain of HER genes.

A

Non-small cell lung cancer.

45
Q

Give an example of a cancer that arises from large deletion mutations in the kinase domain of HER genes.

A

Glioblastoma.

46
Q

List the cancers that arise from amplification of HER genes.

A

1 - Non-small cell lung cancer.

2 - Glioblastoma.

3 - Colorectal cancer.

47
Q

Why do patients often relapse with tyrosine kinase inhibitor therapy?

A

Because secondary mutations arise that affect the target site of the drugs.

48
Q

Which amino acids of the HER genes are most commonly affected by inframe deletions?

A

Amino acids 747-752.

49
Q

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?

A

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.
50
Q

List 4 treatments for EGFR oncogene addiction in non-small cell lung cancer.

A
  • 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.

51
Q

What is a problem with second generation tyrosine kinase inhibitors?

A

They are relatively toxic.

52
Q

Which amino acids of the HER genes are most commonly affected in glioblastomas?

A

Amino acids 6-73.

53
Q

What is the effect of mutations to the HER gene in glioblastomas?

A
  • 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.

CAN (24 decks)

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