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M2M2 > Clinical Cytogenetics > Flashcards

Clinical Cytogenetics Flashcards

1
Q

Chromosome and FISH studies are important for investigating the causes of (2)

A

Leukemia and Lymphoma

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2
Q

Chromosome microarray is standard of complimentary to chromosome and FISH studies for who?

A

Individuals with developmental delays (including multiple congenital anomalies, autism, intellectual disabilities)

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3
Q

Specimens for Cytogenetic Studies (4)

A

Bone Marrow
Blood
Tissue
Fluids

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4
Q

What tissues are used in cytogenetic studies for cancer diagnostics (5)

A 
Bone marrow
Unstimulated Blood
Lymph node tissue
Solid tumor tissue
CNS fluid
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5
Q

When we are looking and leukemia and lymphoma, we usually see block in 3 points of differentiation in hematopoietic lineages, what are they?

A

L blast –> Lymphocyte

Pro-myelocyte –> myelocyte (neutrophil lineage)

Megakaryocyte –> platelet

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6
Q

What are two common cytogenetic findings in childhood B-cell leukemia?

A

Low hypodiploidy

High hyperdiploidy

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7
Q

Low hypodiploidy or near triploidy in Childhood B-cell acute lymphocytic leukemia is associated with what prognosis

A

Poor Prognosis

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8
Q

Poor prognosis in Childhood B-Cell ALL is associated with what cytogenic finding?

A

Low hypodiploidy or near triploidy

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9
Q

In cases of pediatric B-cell acute lymphocytic leukemia (ALL) what is associated with a good prognosis?

A

High hyperdiploidy (e.g. >50) - specifically 4,10,17

*but not that near triploidy is associated with poor

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10
Q

What childhood disease has cytogenetic studies helped to improve dramatically (i.e. 95% remission)

A

Childhood ALL

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11
Q

So in addition to diagnosis, cytogenetics is important in prognosis and treatment protocol
One example being Childhood ALL
If Hypodiploid ?
If Hyperdiploid?

A

Hypo - poor prog –> high dose chem

Hyper - good prog –> low dose chem

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12
Q

When we do cytogenetic studies, in addition to finding cells with abnormal chromosomal constitutions we also find cells with normal 46XXorY constitutions, what is this called?

A

Somatic mosaicism

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13
Q

Suppose a 3 year old presented with leg and arm pain / fever / abdomen distension / and 48% BLASTS? What would this be indicative of?

A

ALL

Blasts should be no more than 1%

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14
Q

FISH =

A

Florescence in situ hybridization

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15
Q

What does FISH do?

A

Specific, cloned DNA sequences can enumerate number of a specific chromosome OR identify translocation!

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16
Q

Types of FISH probes (5)

A 
Centromere
Locus specific
Dual fusion/fusion
Break apart
Whole chromosome paint
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17
Q

Chromosome analysis of ______________ is performed to detect common anomalies associated with leukemia and lymphoma

A

Bone marrow

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18
Q

What studies can reveal the high hyperdiploidy in Childhood B-Cell ALL?

A

chromosome and FISH analysis

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19
Q

What are two of the most common leukemia translocations?

A

t(9;22) is diagnostic for chronic myelogenous leukemia (CML) - which can be treated with tryrosine kinase inhibitors

t(15;17) is diagnostic for a specific acute promyeloid leukemia (APML), which can be treated with retinoic acid

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20
Q

Centromere FISH probes are used for___________

example?

A

Enumeration

All panel

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21
Q

Locus specific FISH probes are used for?

A

Deletion / duplication detection

e.g. p53

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22
Q

Dual fusion / fusion (DF, F) FISH probes are used for?

example (2)

A

Translocation detection

BCR;ABL
PML;RAR

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23
Q

Break apart FISH probes are used for?

A

Translocation rearragement

MLL

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24
Q

Whole chormosome paint FISH probes are used for?

A

Identifying markers / translocations

WCP 1-22,X,Y (all studies)

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25
Q

Two significant effects of translocations

A

Altered gene expression (e.g. translocated next to a strong enhancer or promoter)
Creation of novel fusion product

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26
Q

What kind of probe would we use for BCR;ABL FISH?

A

Dual fusion

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27
Q

What does it mean for a translocation to be cryptic and what do we need to detect?

A

Cryptic translocations result in normal looking karyotypes because translocated regions were equal in size and I would assume had similar banding
Thus, we need FISH to detect these
e.g. t(12;21)(p13;q22) in ALL

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28
Q

Acute Myelogenous Leukemia

Do we see this in adults or kids?

A

More frequently adults but also in children/young adults

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29
Q

What are the two chromosomal aberrations that we focused on?

A

t(15;17)(q22;q21) PML-RARalpha (4.1%)

t(9;22)(q34;q11) ABL1;BCR (0.7%)

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30
Q

What are auer rods?

A

They show up on path slides, they are suggestive of myeloid disorder - acute promyelocytic leukemia (APML)

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31
Q

What is the 9;22 tranlocation called?

A

Philidelphia chromosome

32
Q

What is the t(9;22) consistent with?

A

Diagnosis of chronic myelogenous leukemia

33
Q

What chromosomal aberration is characteristic of APML (Acute promyelocytic Leukemia)?

A

PML/RAR rearrangement

t(15;17)

34
Q

What is the consequence of PML/RARa rearrangement?

A

Myelodi Hematopoietic precursor differentiation blockage
The PML-RARa fusion protein seems to interrupt the differentiation of myeloid hematopoietic precursors past the promyelocytic stage

35
Q

How do we treat patients with PML/RARa

A

Treatment of APML patients with retinoic acid apparently overcomes the inhibition of the fusion protein and allows differentiation of myeloid precursors

36
Q

What is a common secondary cytogenetic abnormality in cases with t(15;17)

A

Trisomy 8

37
Q

What common secondary cytogenetic abnormalities do we see in CML

A

Trisomy 8

38
Q

Why does BCR;ABL yield cancer?

A

The activity of tyrosine kinases is typically controlled by other molecules, but the mutant tyrosine kinase of the BCR-Abl transcript codes for a protein that is “always on” or continuously activated, which results in unregulated cell division (i.e. cancer).

39
Q

Imantinib (Gleevac)

A

Treats CML
Binds ATP binding site in abl tyrosine kinase and bcr/abl tyrosine kinase
Inhibits cell proliferation

40
Q

DS infants and children are at elevated risk for which cancers?

A

20-100x for ALL or AML
500x for AMKL
Note: FISH studies only demonstrate gain of 21 sequences - so maybe something else going on?

41
Q

CMA - what is on slide?

A

Target DNA - single stranded oligomers

42
Q

CMA - what does it detect?

A

Gains and Losses (ONLY!)

43
Q

Can CMA detect re-arrangements?

A

NO

44
Q

Can CMA detect mosaicism

A

Limited (10-15%)

45
Q

Compare and Contrast
Cytogenetics and CMA
What are we screening?

A

Both screen the genome

46
Q

Compare and Contrast
Cytogenetics and CMA
What phase are we screening?

A

Cytogenetics - mitotic

CMA - interphase

47
Q

Compare and Contrast
Cytogenetics and CMA
What cells do we screen?

A

Cyto - selected cells

CMA - all cells

48
Q

Compare and Contrast
Cytogenetics and CMA
What are we looking for?

A

Cyto - Gain/Loss and Balanced Rearrangement

CMA - Gain/Loss only

49
Q

Compare and Contrast
Cytogenetics and CMA
Accuracy

A

Cyto - Technologist expertise

CMA - technology

50
Q

What are runs of homozygosity?

A

Runs of homozygosity (ROH) are long stretches of consecutive homozygous genotypes probably reflecting segments shared identically by descent as the result of processes such as consanguinity, population size reduction, and natural selection.

51
Q

CMA can detect what?

A

Runs of homozygosity because they contain SNPs

52
Q

What is the advantage of chromosomal microarrays?

A

Detects chromosomal gains and losses, some of which my be “Submicroscopic” -
One array = 850,000 FISH studies
Intensity and allelic imbalance

53
Q

Chromosomal microarrays detects abnormalities in known hot spots - what are known hot spots?

A

Areas of known genetic disease

e.g. 22q11.2 deletion

54
Q

Chromosomal microarrays can be used to characterize chromosome abnormalities detected by karyotyping - what does this mean?

A

Can detect specific size of imbalance and genes involved

55
Q

Current CMAs use ________ based platform to interrogate over 850,000 regions of the genome

A

SNP

56
Q

CMA methods

What is our sample, usually?

A

Peripheral blood

57
Q

CMA methods - what are we comparing

A

Spots/Color intensity of sample DNA to 50 normal individuals

58
Q

CMA methods - the SNP platform provides information on intensity and on runs of homozygosity, which might possibly reveal?

A

Autosomal recessive conditions

59
Q

CMA frequently reveals ________-and _____________ of genetic material that cannot be seen by standard cytogenetics and light microscopy

A

deletions and duplications

60
Q

Copy number variants

A

duplications or deletions within the DNA for which there can be associated pathology or no consequence - depending on location and size

61
Q

Can you detect copy number variants at the chromosomal level?

A

NO

62
Q

CNV are there regions of known clinical significance?

A

Yes
There are regions known to be del/dup associated with Mendelian disorders
Also Tumor susceptible loci

63
Q

CMA Reports

Determine what?

A

Size and location of deletion/duplication (most >200Kbp) –> leads to further investigation of data base

64
Q

CMA reports - look for genomic content of region

A

Copy number variants?
Gene/functions
Known phenotypes

65
Q

CMA reports and heritability

A

Is de novo or inherited?

66
Q

Chromosomal microarray - drop in florescent signal at given chromosomal region indicates?

A

Dropout - deletion

Loss of segment of chromosome DNA

67
Q

If possible, what do we always follow up CMA test with?

A

FISH Confirmation

68
Q

So if a child comes in with developmental delay, autism, and dysmorphic features, we first do A and then do B lastly C

A

A. CMA
B. Metaphase FISH confirmation
C. Look at database of genomic variants for relevant deletions / diseases

69
Q

CMA reports determine _ and _ and are supported by multiple levels of __

A

size and location of deletions and duplication and are supported by multiple levels of SNP

70
Q

CMA lab reports thresholds

A

Deletion >200kb
Duplications>400 kb
smaller findings in clinically significant regions

71
Q

CMA lab reports ROH

A

Evaluated at >5Mb with reporting threshold 10Mb

Total % ROH reported if >5%

72
Q

CMA cannote detect (3)

A

low level mosaicism
heterodisomy
balanced chromosome rearrangements

73
Q

CMA reports

Genomic content of regions (2)

A

Copy number varians

Genes/functions

74
Q

CMA reports

Heredity?

A

De novo or inherited

75
Q

Can we see point mutations with fish?

A

No, probes are 200kb so would still hyrbidize? strange since it is SNP platform

M2M2 (27 decks)

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