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1PATH3305 Medical Genetics > Lecture 14: Cytogenetics of Cancer > Flashcards

Lecture 14: Cytogenetics of Cancer Flashcards

1
Q

Semantics;

definition of ‘mosaic’

A

an art of decoration
with small pieces of coloured glass, stone or other materials

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2
Q

Definition of genetic mosaicism

A

Mosaicism -
- presence of TWO OR MORE CELL POPULATIONS (I),
- each with its “PERSONAL” genome, in
- an individual DEVELOPED FROM A SINGLE FERTILISED EGG (II)

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3
Q

How is genetic mosaicism DISTINGUISHED FROM CHIMERA?

EXAMPLES? 2

A
  • Distinguish from chimera – TWO OR MORE CELL POPULATIONS (I)….’DERIVED FROM DISTINCT FERTILISED EGGS’ (III)

e.g.
– fusion of DZ twins
– transplantation

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4
Q

Acquiring mosaicism…ERRORS OCCURRING IN: 3

A

1 – Stem cells (body-wide mosaicism)

2 – Differentiating cells (tissue-specific)

3 – Differentiated cells (organ-specific)

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5
Q

Distribution of mosaicism…

‘as seen on diagram slide 6’
= 3

A
  • a) somatic
  • b) somatic + germline
  • c) germline (gonadal)
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6
Q

MOLECULAR CLASSES of DISEASE ASSOCIATED mosaicism = 5

A

1 * Mendelian ( point mutations/small indels)

2 * Chromosomal / CNV

3 * Epigenetic (imprinting)

4 * Mitochondrial – heteroplasmy

5 * Complex - combination of different molecular classes

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7
Q

Health impact of mosaicism = 3

A

1 * Non-pathogenic
– X-chromosome inactivation
– Immunogenetic mosaicism
– Complexity of neuronal cell types (somatic retrotransposition)

2 * Pathogenic
– Disorders exclusively associated with mosaicism, i.e. Pallister-Killian syndrome

3 – Cancer

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8
Q

Health impact of mosaicism: NON-PATHOGENIC…3

A
  • Non-pathogenic

1 – X-chromosome inactivation

2 – Immunogenetic mosaicism

3 – Complexity of neuronal cell types (somatic
retrotransposition)

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9
Q

Health impact of mosaicism: PATHOGENIC

A

– Disorders exclusively associated with mosaicism, i.e. Pallister-Killian syndrome

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10
Q

UNDERSTANDING Cancer cytogenomics: 4

A

1 * Key element for diagnosis (many subtypes of cancer may be distinguished based on underlying abnormalities)

2 * Prognostic value

3 * Detection of a specific abnormality may define
response to therapy

4 * Monitoring for an early detection of disease
relapse or cancer evolution including new abnormalities

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11
Q

Cytogenomic mechanisms of cancer

A

1 * ‘Chimeric gene fusion with oncogenic properties’
- (balanced structural chromosomal rearrangements)

2 * ‘De-regulated oncogene expression’
– Juxta-positioning in the vicinity of an enhancer
(structural rearrangements)
– Amplification (numerical or unbalanced structural
changes)

3 * ‘Tumour-suppressor gene inactivation’
- (numerical or balanced/unbalanced structural changes)

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12
Q

Cytogenomic mechanisms of cancer

‘Chimeric gene fusion with oncogenic properties’

A

(balanced structural chromosomal rearrangements)

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13
Q

Cytogenomic mechanisms of cancer:

‘De-regulated oncogene expression’ 2

A

1 – Juxta-positioning in the vicinity of an enhancer
(structural rearrangements)

2 – Amplification (numerical or unbalanced structural
changes)

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14
Q

Cytogenomic mechanisms of cancer:

‘Tumour suppressor gene inactivation’

A

Tumour-suppressor gene inactivation

  • (numerical or balanced/unbalanced structural changes)
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15
Q

Gene fusion:

“Philadelphia” chromosome (Ph’)

(in haematological malignancies)

A
  • Balanced translocation
  • aberrant activation of cell signalling
    – t(9;22) = chromosome 9 and 22 translocation
    – BCR-ABL1 mRNA
    – BCR-ABL1 protein
    – Activation of downstream pathways

DIAGRAM ON SLIDE 11

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16
Q

Clinical implications of Ph

A

Ph’ = Philadelphia chromosome

  1. Chronic Myelogenous Leukaemia (CML)
  2. Acute Lymphoblastic Leukaemia (ALL)
17
Q

Clinical implications of Ph’

— Chronic Myelogenous Leukaemia (CML)? = 3

A
  1. Increased incidence >50 years of age
  2. 95% Ph’+ve
  3. Good prognosis if Ph’+
18
Q

Clinical implications of Ph’:

Acute Lymphoblastic Leukaemia (ALL) = 3

A
  1. 30% of adult ALL Ph’+ve
  2. 6% of child ALL Ph’+ve
  3. Poor prognosis if Ph’+ve
19
Q

Ph’ BCR-ABL1 fusion(s)

SLIDE 13

A

BCR = m-bcr minor, M-bcr major, micro-bcr micro
– CHROMOSOME 22q11

ABL = frequent Abl breakpoints
CHROMOSOME9q34

COMMON IN ALL e1a2 transcript, p190

Common in CML p210
- e13a2 (b2a2)
-e14a2 (b3a2) transcripts

e19a2 transcript ..p230

neutrophils increase
thrombocytes increase

IMPORTANT DIAGRAM

20
Q

Ph’ detection by FISH:
‘Major’ BCR breakpoint

UNDERSTAND DIAGRAM ON SLIDE 14

A

9q34 region = 671kb
- ASS1 …Exon 1b…Exon 1a… Exon 2 ..Exon 11

22q11 region = 287 kb
- exon 1 ….mbor region …exon 2 …exon 3 …m-bor region …3’

21
Q

Ph’ detection by FISH:
‘Minor’ BCR breakpoint…

UNDERSTAND DIAGRAM ON SLIDE 15

A

9q34 region = 671kb
- ASS1 …Exon 1b…Exon 1a… Exon 2 ..Exon 11

22q11 region = 287 kb
- exon 1 ….mbor region …exon 2 …exon 3 …m-bor region …3’

22
Q

Ph’-specific therapy?

A

Nucleus = chr 22, and chr 9 …translocation …philadelphia chro, with BCR-ABL

Cytoplasm = BCR-ABL PROTEIN
- ‘Tyrosine kinase inhibitors’

  • DOWNSTREAM ACTIVATION
  • Inhibitors of downstream signalling pathways
    …
    JAK/STAT
    PI3K/AKT
    RAS/MEK
    mTOR
    Src Kinases

DIAGRAM ON SLIDE 16

23
Q

Cytogenomic abnormalities in the monitoring of disease progression…

A

important diagram on slide 17

Heamatological response
CHR
Cytogenetic response
CCyR
Molecular response
MMR (MR^3)
MR^4
MR^4-5
MR^5
?

the above list goes down these scales…

  • Log reduction 0-6..
  • BCR-ABL1% level…100%- 0.00001%
  • Leukaemia cells
    10^13 ….to 10^6…0
    CHR, complete

haematological response; CCyR, complete cytogenetic response; MMR, major molecular response;
MR, molecular response with the number indicating log-reduction on the International Scale (IS)

24
Q

Oncogene juxta-positioning to an enhancer

A
  1. Burkitt lymphoma (bone marrow)
  2. MYC (8q24) (from;)
    • IGH (14q32)… chr 8 and 14 translocation t(8;14)
  • IGK (2p12)… chr 2 and chr 8 translocation t(2;8)
  • IGL (22q11)… chr 8 and chr 22 translocation t(8;22)

diagram on slide 18..important

25
Q

Immunoglobulin gene enhancer-upregulated ‘MYC’ expression

A

Aberrant activation of a transcription factor

-t(8;14)
- MYC
- MYC mRNA
- MYC protein
- Aberrant expression of MYC target genes

diagram on slide 19

26
Q

Oncogene amplification

A

Duplication:
MYCN (2p24.3)

—> ‘Double minutes’

and/or

—> ‘homogeneously stained region’
(diagram 20: no abnormality vs homogeneously stained region’)

then
‘NEUROBLASTOMA: most common solid tumour in children’

27
Q

Tumour-suppressor inactivation:

A

RETINOBLASTOMA

  • due to RB1 (13q14.2)
    chr 13, del(13)

RB- functional allele
rb - mutated allele

Germline = 1st rb + RB –> CONSITUTIONAL = RB rb —> 2nd —> TUMOR = rb rb

LOOK AT DIAGRAM ON SLIDE 21

GERMLINE, CONSITUTIONAL, TUMOR

2 OTHER WAYS

28
Q

The master catastrophic event in cancer: chromothripsis

A
  1. unperturbed chromosome
    ….
  2. CHROMOSOME SHATTERING
    ….
  3. CHROMOSOME REASSEMBLY
    ….
  4. TRUNCATED REARRANGED CHROMSOMES

= CAN LEAD TO
1. Double minutes
2. deletion
or ‘GENE CHANGE OF FUNCTION DUE TO’
3. fusion
4. disruption

DIAGRAM ON SLIDE 22

29
Q

Chromothripsis is detected by genomic technologies
(SNP microarray and/or whole genome sequencing)

A
  • CHR 14
  • no copy number change
  • rearrangment links for changes: GAIN, LOSS, INVERSION
  • GLIOBLASTOMA:
    MOST COMMON MALIGNANT BRAIN TUMOUR IN ADULTS

DIAGRAM ON SLIDE 23

30
Q

Epigenetic defects and cancer:

gestational trophoblastic disease

A

GESTATIONAL TROPHOBLASTIC DISEASE (GTD)

  • malignant
  • premaligant

DIAGRAM ON SLIDE 24 ..FLOW CHART

31
Q

Partial moles: diandric triplody

A

Partial moles: diandric triplody

  • 18x3, XYY
  • 13x3, 21x3

pathology outlines..partial hydatidiform mole

32
Q

Special cases - 2 cases

A
  1. CHROMOSOME INSTABILITY
    - leads to DNA-REPAIR DISORDERS
    - ‘breaks and chromatid interchange’
    = FANCONI ANAEMIA
  2. REPLICATION DISORDERS
    - patient vs control diagram slide 26
    = BLOOM SYNDROME
33
Q
  1. Cancer is associates with …..?
  2. MECHANSIMS?
  3. Challenges?
  4. detection of…provide clues for…
A

1 * Cancer is associates with somatic mosaicism and cytogenomic abnormalities

2 * Various underlying mechanisms

3 * Diagnostic challenges

4 * Detection of ‘cytogenomic abnormalities’ in
cancer provides clues for: ‘Dx, prognosis, therapy and disease evolution’

1PATH3305 Medical Genetics (20 decks)

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