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[ONCG2002] Cancer Cell Genetics > 4: Mechanisms Of Oncogene Activation, Function, And Relation To Cancer I > Flashcards

4: Mechanisms Of Oncogene Activation, Function, And Relation To Cancer I Flashcards

1
Q

Why does cancer incidence increase with age?

A

Older people have undergone more divisions of their cells, therefore there is an increased chance of mutation during those divisions

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2
Q

What are mutations

A

Permanent changes to the DNA sequence of a gene

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3
Q

What are the 6 forms of mutations

A
  • Single nucleotide variations
  • Insertions/deletions
  • Transolocations
  • Aneuploidy
  • Microsatellite instability
  • Gene amplification
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4
Q

What is a single nucleotide mutation

A

A substitution of he base at an individual nucleotide
Eg CTG > CAG

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5
Q

What are insertions/deletions

A

The gain/loss of one or more nucleotides

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6
Q

What are translocations

A

The rearrangement of non-homologous chromosomes
(DNA of chromosomes switch)

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7
Q

What is Aneuploidy

A

The gain/loss of whole chromosomes

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8
Q

What is microsatellite instability?

A

Variation in short repeats found within the genome.

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9
Q

What is gene amplification

A

Many copies of the section containing the gene exist

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10
Q

What is a missense mutation

A

1 amino acid is changed in the point

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11
Q

What causes a nonsense mutation?

A

Where the mutated gene codes for a stop codon.

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12
Q

What is a frame shift mutation

A

Where the removal/addition of a base pair changes all amino acids after the mutation, the shift of the reading frame

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13
Q

What types of mutation often causes a loss of function?

A

Nonsense and frameshift

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14
Q

What type of mutation is likely to cause a gain of function?

A

Missense

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15
Q

What is a silent change in the coding region?

A

Where a point mutation changes a base pair, but the codon translates into the same amino acid.

This is due to the genetic code being degenerate.

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16
Q

Can silent change mutations make a difference to the formation of its protein?

A

A silent change will still produce the same amino acid, so the structure of the protein produced remains the same.

However, the tRNAs required for the different codons may vary in abundance, so rate of translation may be affected.

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17
Q

Oncogenes are typically activated, therefore if point mutations occur, what sort of mutation are they likely to be?

A

Missense
(Gain of function)

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18
Q

What are the 3 common isoforms of Ras?

A

K-Ras
N-Ras
H-Ras

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19
Q

What is G(N)EF and what does it do?

A

Guanine-nucleotide exchange factor

Promotes the release of GDP from Ras, and from the Ras catalytic pocket. This means the relative abundance of intracellular GTP compared to GDP ensures the binding of GTP to Ras

Switches Ras on

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20
Q

What are GAPs and what do they do?

A

GTPase-activating proteins

Promotes GTP hydrolysis. They accelerate the hydrolysis of GTP, therefore are negative regulators of Ras functions.

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21
Q

Which regulators promote and demote the functions of Ras?

A

Promote: GEF (Guanine-nucleotide exchange factors)
Demote: GAP (GTPase activating proteins)

22
Q

Outline the normal Ras signalling.

A
  • Inactive Ras is bound to GDP.
  • Guanine-nucleotide Exchange Factors promote the preferential binding of GTP to Ras, instead of GDP.
  • Ras is activated
  • Downstream signalling pathways of Ras are activated
  • GTPase activating proteins promote the hydrolysis of GTP, meaning Ras binds to GDP, inactivating Ras and its functions.
23
Q

Outline oncogenic Ras signalling

A

GTPase is unable to bind to the Ras-GTP.
Ras remains in its active state, bound to GTP.
The cell loses its ability to regulate the Ras signalling pathways.

24
Q

What can ERK activation lead to?

A
  • Increased DNA synthesis
  • Increased cell proliferation
25
Q

Where do the majority of Ras mutations occur?

A

In position 12 (G12C/G12V), its active site.

26
Q

How come you can’t diagnose a cancer from its Ras mutation?

A

There may be multiple/different Ras isomers mutated in the same cancer.

27
Q

What cancer has the highest % of Ras mutations in all its cases?

A

Pancreatic ductal adenocarcinoma - 98% of cases have mutations in K-Ras

28
Q

Describe how drugs may be used to combat Ras mutations in cancer

A

It is difficult to target the Ras protein itself, so other methods can be used:
- Block receptors of Ras
- Target the signally pathways that oncogenic Ras causes

29
Q

What is gene amplification?

A

Gain of copies of a gene(s) by unbalanced cytogenetic abnormality

30
Q

Define cytogenetics

A

how the chromosomes relate to cell behaviour, particularly during mitosis and meiosis.

31
Q

Why is the definition of amplification different for different diseases?

A

Some diseases may only be defined by 1 extra copy of the gene, whereas another may be multiple extra copies, so it cannot be defined by a specific number for all diseases

32
Q

In what cancers has observed gene amplification of n-myc?

A

Childhood cancers eg:
Retinoblastoma
Glioblastoma
Medullablastoma

33
Q

What is n-myc

A

A transcription factor

34
Q

What happens when n-myc is amplified?

A

Usually n-myc only binds to 2 target genes, but when it is amplified it is less specific and binds to a number of additional E-box motifs.

It therefore activates the transcription of other genes that wouldn’t be transcribed otherwise

35
Q

What is often the prognosis for patients with n-myc amplification?

A

The prognosis is often poor

36
Q

How does n-myc as a genetic bio marker translate into risk stratification?

A

It is an aggressive cancer, so the treatment must also be aggressive.

As the amplification of n-myc is associated with childhood cancers, clinicians have to be aware the consequences of using aggressive treatment for children patients, and to consider he side effects differently to adult patients

37
Q

What is FISH

A

Fluorescent in-situ hybridization

38
Q

What is FISH used for?

A

To mark and count the number of copies present in a patient’s cells

39
Q

Briefly outline how FISH works in a cell

A

The fluorescent tag is on a piece o probe DNA, which is complimentary to the target sequence.

The DNA is denatured, so that the probe DNA can bind, and the fluorescent tag is visible on chromosomes with the N-myc gene present

40
Q

Why is the prognosis of n-myc amplification often poor?

A

N-myc feeds into many pathways (metastasis, angiogenesis, pluripotent, proliferation, etc), which negatively affects the prognosis of a patient.

41
Q

Briefly outline the pathways of tyrosine kinases.

A
  • tyrosine kinase recognises and binds to the tyrosine phosphorylation site on a substrate
  • catalyzes the transfer of a phosphate group from ATP to hydroxyl group on the tyrosine.
  • his alters the charge and structure of tyrosine-substrate, affecting its function
42
Q

How might the phosphorylation of a substrate with tyrosine affect the protein’s activity and function?

A
  • activation or inactivation
  • modulation of binding affinity
  • changes in conformation
43
Q

What does the Ras-MAPK pathway leads to?

A

gene transcription and cell proliferation.

44
Q

What does the P13K-Art pathway promote?

A

cell survival and growth.

45
Q

What are some examples of receptor tyrosine kinases? (RTKs)

A
  • EGFR
  • c-kit
  • VEGFR
  • FLT3
46
Q

What s an example of a non-receptor tyrosine kinase?

A

BCR-ABL

47
Q

Outline the RTK pathway

A
  1. Receptor activation: external ligand binds to receptor protein, inducing dimerization
  2. The dimerized receptors auto-phosphorylated tyrosine residues on each other
  3. They serve as docking sites for adaptor proteins (eg Grb2/Shc) which are recruited to the receptor
  4. Adaptor proteins facilitate activation of downstream signalling pathways (eg Ras-MAPK or P13-Akt)
  5. Signalling pathways initiated may involve secondary messenger systems (eg cAMP/ calcium signalling)
  6. Signalling pathways effect cellular responses eg cell growth, differentiation, survival, proliferation
48
Q

What happens when RTKs mutate?

A

The ligand is no longer needed, ad the micro environment of the cell no longer affects activity. Activiation is always turned on in the absence of the ligand

49
Q

Why are mutations in tyrosine kinases clinically important?

A
  • They are easier to target than a TF or GPase
  • Many new targeted therapies in cancer nvolve growing kinases
  • They have many oncogenic activities which can be targeted to prevent cancer
50
Q

What cancer is EGFR inhibitors licensed to be used upon ?

A

Non-small cell lung carcinoma with EGFR mutations present

51
Q

What % of breast cancer has amplification/over-expression of HER2?

A

25%

[ONCG2002] Cancer Cell Genetics (6 decks)

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