Lecture 16- Chromosomes in Cancer Flashcards Preview

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Flashcards in Lecture 16- Chromosomes in Cancer Deck (29)
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1
Q

Philadelphia Chromosome

A

Myeloid Leukaemia

2
Q

Haematopoiesis

A

all arises from haematopoetic stem cell

3
Q

Leukaemia -

A

Stem Cell cancers and then problems arise further down

4
Q

2 types of Leukaemia

A

Either lymphoid or myeloid

-Lymphomas or myeloproliferative disorders

5
Q

What dictates the cancer and the prognosis ?

A

Stage in the cell it matures in dictates the cancer and the prognosis the later it occurs in the cell the worse the prognosis

6
Q

Multiple Myeloma

A

of the plasma cells

7
Q

What is the more common form of Leukaemia ?

A

Myeloid leukaemia more common – more cell types involved > granulocytes eg eosinophils, basophils, neutrophils
-Accumulation of the immature cell types – myeloid progenitor induced to produce more cells but they don’t mature – blasts are cells that haven’t matured

8
Q

Genetic Changes in Leukaemia

A

 Loss of chromosome material
 Gain of chromosome material – duplication, amplification and trisomy
 Altered gene expression – gene fusion, juxtaposed (next to new gene control)
 DNA mutation – point, splice, frameshift, deletion, duplication

9
Q

Testing for Chromosome Abnormalities

A

 Cytogenetics – study of genetic material and chromosome level
 Karyotype – whole genome scan
 Fish

10
Q

Preparation of the karyotype

A

Want chromosomes at metaphase – add colcemid

Sample > Culture medium > Incubate 37> Add colcemid > Add hypotonic sol > Fix cells > stain> Banding > Karotyping

11
Q

Dark bands

A

AT rich, late replication, gene poor, heterochromatic

12
Q

Light Bands

A

GC rich early replicating, gene rich

Euchromatic

13
Q

Trypsin produces…

A

Dark and light bands

14
Q

Karyotype analysis

A

Analysis- count and pair chromosomes

Match up bands look for absent/extra

15
Q

Types of chromosome abnormalities

A
  • Trisomy
  • Monosomy
  • Inversion
  • Insertion – chunk of one chromosome into another
  • Translocation – swap of chromosome from one to the other
16
Q

Chromosome nomenclature

A
	Long arm q 
	Short arm p 
	Each band assigned a number e.g 3p21 
	46 chromosomes 
	Autosomes 1-22
and sex chromosomes – XX or XY 
total number, sex ,abnormality
17
Q

Fusion genes

A

breakpoint occurs with the two genes and forms a hybrid

18
Q

Deregulation

A

juxtaposition to a regulating gene altered regulation

19
Q

Detection –

A
  • Translocation and inversions via karyotype
  • Some gene fusions are caused by subkarotypic rearrangements
  • Clinical need for rapid confirmation of gene fusion – prognostic and treatment implication
  • FISH
20
Q

FISH

A

 Fluorescently labelled DNA probes
 Detect monosomy trisomy deletions duplication, amplification and rearrangement s
 Probe is ssDNA probe
 Probe on slide cover with cover slip and then hybridise over night

21
Q

Types of FISH probe

A
  • Whole chromosome paints
  • Locus specific
  • Break a part probes – detect gene fusion > Dual colour probe – abnormal translocation, probe broken apart
    KMT2A – doesn’t matter what its fused with just the translocation isn’t good
22
Q

Digital Droplet PCR

A

very sensitive > probe for mutant and Wt added to PCR action components – partitioned into oil droplets one PCR reaction per droplet
WT probe only binds to WT and same for mutant
Measured by fluorescent detection
- Can predict relapse

23
Q

Next generation sequencing

A

look at technique used for myeloid panel look for specific mutation s not shown in karyotyping
- More at once

24
Q

Purpose of genetic testing

A

 Prognostic
 Diagnostic
 Monitoring

25
Q

Real time quantitative PCR

A

quantify DNA molecules present- used to monitor response to therapy

26
Q

BCR-ABL Quantitation

A

Q-PCR is used to measure BCR/ABL transcript in monitoring of disease during treatment in CML

27
Q

Chronic Myeloid Leukaemia (CML)

A

1960 Nowell and Hungerford
Small chromosome named the Philadelphia chromosome (Ph)
First evidence for a consistent chromosome change

1970 introduction of banding

28
Q

PH Translocation

A

Fusion of two genes:
ABL1 (9q34)
BCR (22q11)

ABL1 is a cellular oncogene and encodes a nuclear tyrosine kinase protein
BCR/ABL1 gives an abnormal fusion protein with increased tyrosine kinase activity
Is a positive regulator of cell growth and leads to increased proliferation and malignant growth
Alone, is sufficient to cause CML

29
Q

Targeted therapy for BCR-ABL1

A

2001- introduction of Imatinib
Specific inhibitor of of tyrosine kinase domain of ABL1
Blocks the binding site for ATP and inhibits phosphorylation
Prevents activation of the signal transduction pathways