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
Immunoglobulin gene enhancer-upregulated 'MYC' expression
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
Oncogene amplification
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
Tumour-suppressor inactivation:
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
The master catastrophic event in cancer: chromothripsis
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
Chromothripsis is detected by genomic technologies (SNP microarray and/or whole genome sequencing)
- 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
Epigenetic defects and cancer: gestational trophoblastic disease
GESTATIONAL TROPHOBLASTIC DISEASE (GTD) - malignant - premaligant DIAGRAM ON SLIDE 24 ..FLOW CHART
31
Partial moles: diandric triplody
Partial moles: diandric triplody - 18x3, XYY - 13x3, 21x3 pathology outlines..partial hydatidiform mole
32
Special cases - 2 cases
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
1. Cancer is associates with .....? 2. MECHANSIMS? 3. Challenges? 4. detection of...provide clues for...
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'