Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

EXMD504 > 7. Chromosomal Aberrations > Flashcards

7. Chromosomal Aberrations Flashcards

1
Q

describe a circus plot

A

outside ring shows all human chromosomes
- blue = deletions, red = gains
- intensity of red/blue = amount of tumours with that deletion or gain
- purple lines show chromosomal translocations

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

describe the packing of chromatin

A
  1. 30nm fiber forms series of loops that fold to compact the chromatin
  2. loops wrap around histone proteins
  3. 300nm fiber has multiple loops
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what are the 2 major functions of packing chromatin

A
  1. packages linear info so it occupies as little space as possible
  2. make specific domains with specific functions
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

why is it important that specific regions of chromatin contacts other regions of chromatin

A

for DNA organization and timing of metabolism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

what is the assay for determining the specific localization of diff chromosomes? (3 steps)

A
  1. make tiny damage in nuclei to damage the DNA in small spots
  2. fed cells with radiolabelled nucleotides
  3. when DNA was repaired, the areas where DNA was damaged could be detected
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

what were the 2 hypotheses for localization of chromosomes?

A
  1. all chromosomes have distinct locations in nucleus
  2. all chromosomes are loose and mixed together
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

what does the radiolabelling assay show if chromosomes have distinct locations?

A

will see damage on very few chromosomes bc the damage will only be in a certain spot

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

what does the radiolabelling assay show if chromosomes are mixed together?

A

will see damage on all chromosomes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

which hypothesis is correct for the localization of chromosomes?

A

chromosomes are highly organized in specific locations

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

what is the inter-chromatin space?

A

chromosome has loop protruding into inter-chromatin space where processes occur

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

are all chromosomes and different parts of chromosomes in the same regions?

A

diff chromosomes occupy diff regions and diff parts of chromosomes occupy diff regions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

what is the consequence of diff parts of chromosomes occupying diff regions?

A

this affects gene function

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

where are actively-transcribed genes located on the chromosomes?

A

located far from the centromere

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

do chromosomal territories have uniform or varying levels of compactness?

A

chromosomal territories have varying levels of compactness

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

describe the difference in location of early/late-replicating chromatin in chromosomal territories

A

Early –> center of chromosomal territory

Late –> periphery of chromosomal territory

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

how do genes move around?

A

based on metabolism, active genes will move to the surface of convoluted chromatin fibers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

what does the inter-chromatin region contain?(5)

A

complexes and non-chromatin domains for:
1. transcription
2. splicing
3. DNA
4. replication
5. repair

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

what happens to chromatin during mitosis?

A

loose chromatin must form compact, cylindrical, chromosomal bodies that can be sorted into daughter cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

what is Wee1?

A

S phase checkpoint

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

what does Wee1 control? (2)

A
  1. speed of replication fork
  2. replication Common Fragile Site
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

what is the replication Common Fragile Site?

A

this region is replicated late and lags behind –> commonly has mutations

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

why does Wee1 control the replication common fragile site?

A

the common replicating site may still be replicating when the cell wants to divide (bad) so Wee1 controls this

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

what is the spindle assembly checkpoint (SAC)?

A

controls that chromosomes are attached to microtubules for division

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

when is SAC activated?

A

if chromosomes are UNattached

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

what does SAC activation lead to?

A

MCC forms and blocks mitosis by inhibiting cell cycle proteins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

when is SAC inactivated?

A

if chromosomes are attached

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

what does SAC inactivation lead to?

A

MCC is inactivated and mitosis can proceed so chromosomes can separate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

why are all chromosomal aberrations NOT equal?

A

chromosomal aberrations are usually lethal but sometimes a specific combination of chromosomes can make a malignant cell with growth advantage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

describe the first experiment for observing abnormal chromosomes in CML cells and the results

A

chromosomes stained with Giemsa at metaphase stage of mitosis –> detects A-T base pairs

found many patients have small chromosome 22, assumed to be a deletion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

why did they assume the small chromosome 22 was a deletion? what actually occurs in CML?

A

the resolution of the experiment was low so they couldn’t detect that the missing piece of chromosome 22 was actually on chromosome 9 (translocation)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

describe the experiment to determine that the short chromosome 22 was due to translocation?

A

stain with QUINACRINE fluorescence and Giemsa staining to give higher resolution and detect translocations –> can detect BREAK POINT and which genes are affected that

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

what genes were found with the quinacrine+giemsa experiment?

A

BCR on chromosome 22
ABL on chromosome 9

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

describe the BCR and ABL translocations

A

conserved across patients but slightly diff ones with diff molecular weight

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

what gene forms with BCR/ABL fusion

A

gene with 5’ of BCR and 3’ of ABL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

what happens when proteins fuse in frame?

A

domains are translated in the correct open reading frame to make chimeric protein with functional domains from both proteins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

what type of protein is BCR?

A

serine threonine kinase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

what type of protein is ABL?

A

tyrosine kinase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

what do BCR and ABL do normally when not fused?

A

normally, each controls differentiation and proliferation from extracellular signals

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

what do BCR and ABL do when fused?

A

BCR portion activates MAPK

ABL portion activates other survival pathways

less regulation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

3 phases of CML

A
  1. chronic phase
  2. accelerated phase
  3. blast phase
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

what happens during chronic phase of CML?

A

5-6 years

ASYMPTOMATIC

mostly just presence of BCR-ABL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

what happens during accelerated phase of CML?

A

6-9 months

symptoms appear

15-50% of myeloid cells gain new cytogenetic abnormalities

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

what happens during blast crisis of CML?

A

3-6 months

bad cells occupy whole bone marrow and blood and prevent the bone marrow from doing its function –> severe disease

increased genetic instability

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

why do cells with the BCR-ABL fusion protein outcompete the normal cells?

A

BCR-ABL fusion protein acts as a potent ONCOGENE

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

what is Gleevec?

A

kinase inhibitor to block BCR-ABL –> very successful

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

what causes resistance to Gleevec

A

mutation could alter structure of protein or use diff pathway

47
Q

what happens if a patient responds to Gleevec and doesn’t reach accelerated phase of CML after 5 years? why?

A

likely will not reach accelerated phase ever

48
Q

why does the rate of CML relapse depends on the resistant variant at BEGINNING of treatment?

A

at beginning of treatment, there are cells that are already resistant to treatment –> these will outcompete other cells

So the drug can only work if there are cells WITHOUT resistance at the beginning

49
Q

if you don’t relapse, why will you never relapse?

A

if cells without resistance at beginning of treatment can be killed –> the drug is successful and will not relapse

50
Q

where are most mutations in BCR-ABL found?

A

most mutations are found in the kinase domain

51
Q

2 general types of chromosomal aberrations

A
  1. balanced chromosomal rearrangements
  2. chromosomal imbalances
52
Q

2 types of BALANCED CHROMOSOMAL REARRANGEMENTS

A
  1. Formation of chimeric fusion gene
  2. Deregulated expression of structurally normal gene
53
Q

describe deregulated expression of structurally normal gene

A

enhancer hijacking –> breakpoint puts gene under control of diff promoter, enhancer, etc.

54
Q

2 types of chromosomal imbalances

A
  1. gain
  2. loss
55
Q

4 types of genomic GAINS

A
  1. complete trisomy
  2. partial trisomy
  3. intrachromosomal amplification
  4. extrachromosomal amplification
56
Q

what is intrachromosomal amplification?

A

specific region has been amplified, chromosomes look diff

57
Q

what is extrachromosomal amplification?

A

sorted independently of chromosome as an episome

58
Q

3 types of genomic LOSS

A
  1. monosomy
  2. large-scale deletion
  3. submicroscopical deletion
59
Q

what is submicroscopical deletion?

A

can only detect the change by sequencing

60
Q

2 types of chimeric genes generated from chromosomal translocation

A
  1. Involves tyrosine kinase
  2. involves TFs
61
Q

what do chromosomal rearrangements that involve TFs lead to?

A

fusion proteins that cause ENHANCED, ABERRANT, or REPRESSED transcriptional activity

62
Q

describe the FLI1-EWRS1 fusion protein and its role

A

forms chimeric TF

maintains DNA binding domain of FLI1 so it recognizes the same target but has diff transactivation property, causing aberrant expression of genes normally activated by FLI1

63
Q

describe the function of PML-RARA fusion protein

A

conserves DNA binding domain to induce transcription and cause aberrant expression of genes normally activated by RARA

64
Q

what causes deregulated expression of structurally normal gene? and consequence?

A

loses REGULATION, doesn’t lose pieces –> increases selective growth advantage

65
Q

2 examples of deregulated expression of structural normal gene

A
  1. MYC
  2. ERG
66
Q

describe normal MYC and dysregulated MYC

A

normally on chromosome 8 and induces cell survival and proliferation

can be translocated to be under control of heavy chain Ig promoter on chromosome14

67
Q

consequence of dysregulated MYC

A

when B cells want to make heavy chain Ig, they will make MYC instead

68
Q

describe normal ERG and dysregulated ERG

A

normally not expressed in prostate tissue

but translocated to other chromosomes and turned on

69
Q

3 groups of chromosomal aberrations found in sarcomas

A
  1. FUSION-DRIVEN
  2. NON-TRANSLOCATION-ASSOCIATED
  3. HIGHLY UNBALANCED KARYOTYPES
70
Q

how do fusion-driven sarcomas arise?

A

de novo

71
Q

describe the driver event in fusion-driven sarcomas

A

may only have 1 cytogenetic abnormality that is maintained –> the driver event is the fusion event

72
Q

most gene fusions from translocations encode:

A

most gene fusions from translocations encode chimeric TFs that dysregulate genes

73
Q

are gene fusions in sarcomas consistent btwn cases and cells?

A

gene fusions in sarcomas are HIGHLY RECURRENT and found in all cases and cells

74
Q

4 common themes of fusion-driven sarcomas

A
  1. DBD of TF fuses with transactivation domain of another TF to cause changes in gene expression
  2. fusion gene makes constitutively active form of RTK that activates proliferation/survival pathways
  3. fusion gene makes chimeric chromatin regulator
  4. fusion gene enables autocrine mechanism that feeds tumour thru specific growth factors
75
Q

why is a chimeric chromatin regulator different than TF?

A

binds DNA less specifically than TF

76
Q

describe PAX3 and FOXO1 separately and the PAX3-FOXO1 fusion

A

PAX3: TF that directs developmental processes in muscle
FOXO1: TF that is normally regulated thru phosphorylation by AKT

PAX3-FOXO1: DNA binding domain of FOXO1 is lost so PAX3 directs DNA binding

77
Q

is a function of a fusion protein the sum of the 2 proteins?

A

no, there are other factors involved

78
Q

what disease is FLI1-EWSR1 involved in?

A

Ewing-Sarcoma

79
Q

why does FLI1-EWSR1 have unexpected/neomorphic function?

A

fusion protein can bind genes normally targeted by FLI1 but also binds unexpected sites

80
Q

consequence of FLI1-EWSR1

A

opens chromatin labelled by acetylation to turn genes on/off as a pioneer TF

81
Q

what happens if you overexpress FLI1-EWSR1 fusion protein? (2)

A

variable results depending on cell type

on non-Ewing sarcoma cells –> may cause neuronal and endothelial features of gene expression

mesenchymal progenitor cells have most similar expression to Ewing sarcoma cells

82
Q

what happens in non-translocation-associated sarcoma?

A

increased number of chromosomal abnormalities with intermediate genomic complexity

83
Q

what type of sarcoma is commonly non-translocated associated sarcoma?

A

liposarcomas

84
Q

why is genetic complexity “intermediate” in non-translocated-associated liposarcoma?

A

all the abnormalities are in chromosome 12

85
Q

what type of abnormality is in liposarcoma? is it high or low prevalence?

A

gains in chromosome 12 –> high prevalence (90%)

86
Q

what is the non-translocation change that occurs in liposarcoma?

consequence?

A

oncogenes CDK4 and MDM2 are co-amplified on chromosome 12 to inhibit p53

causes cancer with downregulation of p53 tumour suppressor WITHOUT production of a chimeric protein

87
Q

what occurs in sarcoma with highly unbalanced karyotypes?

A

complex genomes with many areas of gains, losses, translocations

often aneuploidy with complex cytogenetic changes that lack specificity

88
Q

what do highly unbalanced karyotype sarcomas often involve?

A

often involves mutated tumour suppressors (p53, Rb)

89
Q

is it common for cancers to have complex karyotypes AND point mutatins?

A

rare

90
Q

what is called when there is a mix of chromosomal abnormalities and point mutations?

A

kataegis

91
Q

describe kataegis

A

hypermutations in regions of structural variants (gain/loss/translocations)

92
Q

is location of structural variants recurrent?

A

no –> not found among all patients

93
Q

do mutations or structural variants occur first in kataegis?

A

structural variants occur first, then mutations occur on top of that

94
Q

besides mutations, what occurs in addition to chromosomal abnormalities? (4)

A

increase of pathways that promote growth:
1. IGF1-receptor pathway
2. PDGFR pathway
3. c-KIT receptor pathway
4. c-MET receptor pathway

95
Q

is the increase of pathways that promote growth independent or related to chromosomal abnormality?

A

the increase of these pathways is independent of chromosomal abnormality

96
Q

5 ways that genomic rearrangements happen in cancer

A
  1. epigenetic modifications
  2. structural configuration
  3. dsDNA breaks
  4. replication stress
  5. ionizing radiation
97
Q

how do structural configurations promote genomic rearrangements?

A

some parts of DNA can be configured to cause more breaks –> non-typical DNA structure

98
Q

how does replications stress promote genomic rearrangements?

A

inefficient replication/replication forks can cause stress in DNA

99
Q

is there one factor that must occur for genomic rearrangement to occur?

A

no, all the diff factors must be combined for rearrangement to occur

100
Q

how does vicinity of genes allow rearrangement? (3 examples)

A

BCR and ABL in close proximity for CML –> fusion protein more likely in this case

In other leukemia, PML and RARA in close proximity –> fusion protein more likely in this case

MYC fuses more with IgH than IgK bc of proximity

101
Q

why are some gene loci brought closer together under certain circumstances?

A

active genes are dynamically organized into shared nuclear SUBCOMPARTMENTS –> rather than recruiting and assembling transcriptional machinery at each site, the genes migrate to pre-assembled transcription and become close to other genes

102
Q

how can cells attenuate effects of chromosomal instability?

A

cells adapt their physiology and homeostasis

103
Q

3 ways cells can adapt their physiology and homeostasis

A
  1. APC/C dysfunction
  2. if aneuploidy, will be making more proteins so take over protein synthesis to trigger apoptosis
  3. near-triploid karyotype
104
Q

describe APC/C dysfunction to attenuate chromosomal instability

A

downstream of spindle assembly checkpoint

NORMAL APC/C
- no mitosis
- allows error correction to prevent excessive chromosomal instability

DYSFUNCTIONAL APC/C
- induces tolerance to chromosomal instability

105
Q

describe how tumour cells induce apoptosis to counteract chromosomal aberrations

A

if aneuploidy and making lots of proteins, will take over ribosomes, protein synthesis, and golgi to trigger apoptosis

i.e. reduce protein load

106
Q

in tumours with high level of chromosomal instability but also high level of tolerance, what type of tumour do we see?

A

faster growth rate and tumour can be maintained –> this is the tumour we see

107
Q

how do tumours adapt to LOW levels of chromosomal instability?

A

low levels of instability are selected against and removed

108
Q

how do tumours adapt to HIGH levels of chromosomal instability?

A

high levels of instability are balanced by tolerance mechanisms

109
Q

what type of cancers are most helpful to diagnose with chromosomal abnormalities? why?

A

sarcoma –> bc high level of chromosomal abnormalities

110
Q

how can we diagnose sarcomas with chromosomal translocations?

A

molecular profiling

use FISH probes to visualize fusion proteins to diagnose diff types

111
Q

how are sarcomas defined? how is this different than carcinomas?

A

defined by their molecular alterations

carcinomas are defined by their organ of origin

112
Q

why is molecular profiling helpful?

A

can see two sarcomas that seem unrelated but find that they both have same translocation leading to same fusion protein

this helps with treatment –> both will have same resistance and transformation mechanisms

113
Q

how are chromosomal abnormalities related to prognosis?

A

chromosomal abnormalities are correlated with outcome

114
Q

2 examples of chromosomal abnormalities correlated to outcome

A
  1. copy number status of chromosome 14 and amplification of Gli2 predicts outcome
  2. amplification of Gli1 family TFs will be resistant to target therapies

EXMD504 (12 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions