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Biology of Cancer > Genome Instability > Flashcards

Genome Instability Flashcards

1
Q

What is genome instability?

A

Refers to unscheduled alterations, either temporary or permanent, within the genome

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2
Q

How do these genome instability appear in cancer?

A
  • All malignant tumour types have been shown to contain chromosomal aberrations
  • The pattern of abnormalities varies greatly between malignancies, ranging from simple rearrangments to complex where both chromosome number and structure is affected
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3
Q

Does changes caused by genome instability affect the tumour?

A
  • May be involved in initiating the tumour
  • Changes accumulate as tumour progresses as tumour cells are more prone to rearrangements compared to normal cells
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4
Q

What are the 2 types of genomic instability?

A
  1. Chromosomal instability (CIN)
  2. Nucleotide level instability
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5
Q

What is chromosomal instability?

A

Gains/losses of whole chromosomes including inversions, deletions, duplications and translocations of large chromosomal segments

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6
Q

What is nucleotide level instability?

A

Mutations of single or small groups of nucleotides (not visible morphologically)

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7
Q

How can you identify complete loss/gain with chromosomal instability?

A

Create a chromosome spread where mitotic chromosomes are laid out and dyed to stain the DNA in order to be able to count each chromosome number

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8
Q

How can you identify translocation with chromosomal instability?

A

Use chromosome painting where each chromosome number is stained a different colour to allow any translocation can be observed

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9
Q

What is balanced translocation?

A

When two chromosomes have broken off and each part has attached to the other chromosome

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10
Q

What is unbalanced translocation?

A

When a part of a chromosome has detached and attached to another but no other part of a chromosome has attached to its original

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11
Q

How can you identify deletion/duplication/inversions with chromosomal instability?

A
  • When chromosomes are stained, there are visible bands of DNA as the grouped DNA is very dense
  • Any DNA that has been deleted/duplicated/inversions on one chromosome can be see when it is compared with the other
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12
Q

How can you identify nucleotide level instability?

A
  • They are small insertions/deletions so can are not visible with a microscope
  • PCR is used to detect these changes
  • Single base changes sequencing can also be used as it will detect the single specific nucleotide that has been altered
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13
Q

What are the effects of point mutations in genome instability?

A
  • Altered gene products (amino acids/proteins)
  • Altered control of the gene product (on/off)
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14
Q

What are the effects of partial/complete deletion in genome instability?

A
  • Loss of gene products
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15
Q

What are the effects of duplications in genome instability?

A
  • Possible interference in balance protein expression (eg chordoma)
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16
Q

What are the effects of inversions/translocations in genome instability?

A
  • Altered gene products
  • Altered gene control
  • Generation fusion proteins with deleterious activities
17
Q

Is genome instability always bad?

A
  • Can be neutral, eg point mutations can give silent mutations or natural variation which will have no effect, especially in non coding areas
  • Can be positive, eg immune cells are able to differentiate in order to protect against any pathogen
18
Q

What 4 processes cause genome instability?

A
  1. Loss of high-fidelity during DNA replication in S phase
  2. Errors during chromosome segregation in mitosis
  3. Uncoordinated cell cycle progression
  4. Error prone repair of sporadic DNA damage
19
Q

How do the different steps of high-fidelity maintenance become unstable?

A
  1. Polymerase accuracy (point mutation)
  2. Mismatch repair (point mutation)
  3. Origin licensing (over/under replication)
  4. Maturation of okasaki fragments (retention RNA)
  5. Restart stalled replication forks (loss of genome)
  6. Re-chromatinisation (stall replication)
  7. Telomere maintenance (loss of sequences)
  8. Preservation epigenetic signatures (lack of accurate transcriptional information)
20
Q

Which process during chromosome segregation in mitosis lead to chromosome instability if not completed properly?

A
  1. Chromosome condensation
  2. Sister chromatic cohesion
  3. Kinetochore assembly and attachment
  4. Centrosome duplication and attachment
  5. Spindle formation
  6. Chromatid segregation
  7. Cytokinesis
21
Q

How do the incomplete processes of mitosis cause chromosome instability?

A

Through chromosome breakage and/or mis-segregation

22
Q

Do these mitotic processes have a large effect on the cell?

A

No, as the faults are usually detected and eradicated by the cell cycle checkpoints

23
Q

What are the 5 cell cycle checkpoints?

A
  1. G1/S checkpoint
  2. G2/M checkpoint
  3. Intra-S checkpoint
  4. Spindle checkpoint
  5. Post mitotic checkpoint
24
Q

What does the G1/S checkpoint check?

A
  • Sufficient energy levels
  • Sufficient nucleotide levels
  • Important protein complexes are in the correct place for replication
25
Q

What does the G2/M checkpoint check?

A
  • Replication is finished
  • Chromosomes are in the right state for separation (condensed)
26
Q

What does the Intra-S checkpoint check?

A
  • No unresolved DNA damage present
  • No stalled replication forks present
27
Q

What does the Spindle checkpoint check?

A
  • Spindles are attached correctly to chromosomes
28
Q

What does the post mitotic checkpoint check?

A
  • Chromosome separation is complete
29
Q

What happens if these checkpoints fail?

A
  • Point mutations may be fixed in the new cells
  • Cells may divide with incomplete replicated DNA which can result in inappropriate chromosome fusions
  • Cells may divide carrying over re-replicated regions of DNA which also results in inappropriate chromosome fusions
  • Cells may divide with chromosomes that are not properly attached to the spindle which results in uneven distribution of chromosomes
30
Q

What is chromothripsis?

A
  • Thousands of clustered chromosomal events occur in one single event in a confined genomic region
  • Cause is unknown but it is suspected that it is due to a catastrophic event
  • This causes the genome to fall apart however the cell repair processes are unable to rearrange them accurately

Biology of Cancer (19 decks)

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