Type the Title of Your Talk Hereaz9194.vo.msecnd.net/pdfs/130401/8.pdf · 4 Cytogenetic Resources...
Transcript of Type the Title of Your Talk Hereaz9194.vo.msecnd.net/pdfs/130401/8.pdf · 4 Cytogenetic Resources...
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The Association for Molecular Pathology Education. Innovation and Improved Patient Care. Advocacy.
www.amp.org
Cytogenetics
Gail H. Vance, MD
Indiana University School of Medicine
April 2013
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Disclosure(s)
In accordance with ACCME guidelines, any individual in a position to influence and/or control the content of this ASCP CME activity has disclosed all relevant financial relationships within the past 12 months with commercial interests that provide products and/or services related to the content of this CME activity.
The individual below has responded that he/she has no relevant financial relationship(s) with commercial interest(s) to disclose:
Gail H. Vance, MD
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Lecture Overview
History
Chromosome Structure/Identification/Nomenclature
Chromosome Abnormalities
Numerical (Meiosis, Mitosis, Nondisjunction)
Structural (Inversions, deletions, translocations).
Syndromes
FISH
Cancer Cytogenetics (Numerical/Structural/Nomenclature)
Gene Amplification
Leukemia/Lymphoma/MM
Chromosomal Microarray analysis
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Cytogenetic Resources
Genetics in Medicine: Thompson & Thompson-7th edition WB Saunders, 2007.
Human Genetics: Vogel & Motulsky, Springer,1997.
Chromosome Abnormalities and Genetic Counseling, Gardner & Sutherland, Oxford, 2012.
WHO-Tumours of Haematopoietic and Lymphoid Tissues, 2002/2008
The Principles of Clinical Cytogenetics. Gersen and Keagle, Humana Press, 2005.
Human Chromosomes, 4th Edition, Miller and Therman, Springer Press, 2001.
Websites http://atlasgeneticsoncology.org/
Mahaffey VJ et al. Leukemia Research 2004; 28:1351-1356
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Prehypotonic Era
Hypotonic Era (1950s) Determined actual number of
chromosomes
Staining Era (1960s) Discovery of trisomy 21 in DS Discovery of Philadelphia chromosome
Banding Era (1970s)
Molecular Era (1980 to date) Extended chromosome analysis Molecular cytogenetics
History of Cytogenetics
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Genomic era 2000-present
Chromosomal Microarrays
CGH arrays
SNP arrays
History of Cytogenetics
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Molecular cytogenetics in clinical diagnostics prognostics
cytogenetics.org.uk
emedicine.medscape.com
fluidigm.com
Cytogenetics FISH Arrays
Sequencing
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History of Cytogenetics
1923 T.S. Painter establishes human chromosome number as 48.
1953 T.C. Hsu accidentally discovers hypotonic treatment to spread chromosomes and lyse RBCs
1956 J. Tijo and A. Levan determine correct number of chromosomes as 46.
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History of Cytogenetics
1959 J. Lejeune identifies trisomy 21 as first clinical cytogenetic syndrome.
1960 P. Nowell identifies small G-group chromosome in CML as the Philadelphia chromosome.
1968 Caspersson utilizes quinicrine mustard to develop Q-banding method.
1971 Paris, 1st nomenclature conf.
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History of Cytogenetics
1973 G-banded chromosomes, J. Rowley identifies the Philadelphia chromosome as t(9;22)(q34;q11.2).
1990 Molecular Cytogenetics era; FISH
1992 Metaphase Comparative Genomic Hybridization (CGH).
1996 24-color karyotype (Spectral Image)
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History of Cytogenetics
2001 CGH BAC arrays
2006-7 CGH Oligo arrays
2007 Molecular karyotyping with SNPs- constitutional abnormalities
2010 Molecular karyotyping in Cancer
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Human Chromosomes
Chromosome means “colored body”.
Contain most of the human DNA
Chromosomes reside in the nucleus
NIHGR website
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Reasons for Referral for Testing
Prenatal Analysis (Amniotic fluid/CVS)
Advanced maternal age (35 yrs and greater)
Abnormal serum triple/quad screen
Abnormal cell-free fetal DNA
Abnormal ultrasound
Family hx of chromosome abnormality.
Maternal anxiety
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Reasons for Referral for Testing
Peripheral blood
Family hx chromosome abnormality
Multiple miscarriages
Birth defect(s)
Unexplained mental retardation
Confirmation of prenatal diagnosis
Ambiguous genitalia
Abnormal growth and development.
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Reasons for Referral for Testing
Cancer (Bone marrow/unstimulated PB/tumor
Anemia (MDS)
Leukemia/Lymphoma
Myeloproliferative disorder (CML,PCV)
Solid tumor
Multiple myeloma
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Chromosome Structure Key Points
A chromosome is formed from a DNA strand.
After replication (S-phase), the strand is duplicated, two sister chromatids formed.
Each chromosome undergoes a series of compression and compaction steps to form the metaphase chromosome.
The nucleosome is the first level of compaction.
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Chromosome Identification
Chromosomes are identified by
Overall size
Placement of the centromere
G-banded pattern
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Centromere Consists of highly repetitive DNA
Contains -satellite DNA on which the kinetochore forms
Interacts with microtubule proteins to move chromosomes during mitosis and meiosis –serves as a mitotic checkpoint
Telomere Maintains the integrity of chromosomes and
prevents them from sticking together
Naming parts of the chromosome
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Chromosome banding techniques were developed in the early 1970’s
Prior to banding chromosomes were identified according to size and shape named A-G groups
Banding allows one to identify homologs and to better differentiate one chromosome from another
Chromosome banding and staining
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Group A Group B
Group C
Group D Group E
Group F Group G
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Chromosome Identification
G-banding Giemsa stain is used to identify the alternating dark and
light bands of the chromosome. Stains AT-rich DNA. Less affinity for GC-rich areas.
Q-banding Produced by a fluorescent stain, similar to G-bands
C-banding Stains centromere and heterochromatin
R-banding Reverse of G-banding. Used in Europe. Good for tips of
the chromosome.
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Chromosome Banding
Q-bright and G-positive bands are AT-rich
G-positive bands-late replicating/LINES
Gene poor
Q-dull and G-negative bands are GC-rich.
G-negative bands-early replicating/SINES
Gene rich
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G-banding
resolution
Adapted from ISCN 1995
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G-banded
metaphase
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G-banded Karyogram
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Q-banded karyogram
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Which one of the following procedures is used as a routine technique for karyotyping using light microscopy?
A. C-banding
B. Fluorescence in situ hybridization
C. G-banding
D. Q-banding
E. NOR staining
Questions
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Which of the following pairs of staining techniques results in opposite staining patterns of chromosomal loci?
A. C &G
B. G & Q
C. Q & C
D. Q & R
E. None of the above.
Question
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Which of the following is NOT characteristic of G-positive bands on the chromosome?
A. Early replicating
B. Correspond to Q-bright areas
C. Includes heterochromatic regions
D. AT-rich
E. Contain LINE repetitive sequences.
Question
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Nomenclature
• Method of communication between cytogeneticists.
• Adhere to nomenclature standards outlined in “International Standards of Cytogenetic Nomenclature”-ISCN, 2013.
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Karyogram: display of mitotic chromosomes of an individual, lined up from the largest to the smallest (1-22) and according to location of centromere
Karyotype: is the use of nomenclature to describe the chromosomal complement
Idiogram: diagrammatic representation of a chromosome
Terminology
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Arms of the chromosome
Short arm = p
Long arm = q
Nomenclature
46,XX – normal female karyotype
46,XY – normal male karyotype
47,XXY – compatible with Klinefelter syndrome
47,XX,+21 – compatible with a female with Down syndrome
46,XY,t(1;2)(q21;q22) – A male with a translocation between the long arms of chromosomes 1 and 2
Karyotype Nomenclature
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Chromosome Abnormalities
Numerical abnormalities Mitotic or meiotic non-disjunction
Inheritance of a marker chromosome
Anaphase lag
Irregular cell cycle/abnormal spindle proteins
Structural Abnormalities Inherited abnormality
Chromosome instability
Abnormal DNA repair/breaks abnormal reunion
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Constitutional Numerical Abnormalities
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Meiosis/Mitosis
Meiosis: One replication and two divisions results in haploid gamete (23 chromosomes.)
Meiosis I: Reduction from 46 to 23 chromosomes
Meiosis II: Equatorial division/ same as mitosis but only 23 chromosomes.
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Mitosis and Meiosis
Mitosis
Meiosis (germ cells only)
2N
2N
N
N
N
N
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Female Meiosis
Begins in utero
Progresses to prophase I (diplotene)
Arrested at 9th month gestation (dictyotene).
Begins again in puberty at ovulation.
Meiosis II completed upon fertilization
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Male Meiosis
Begins at puberty in seminiferous tubules
Goes through completion in 64 days
Continues late in life
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Nondisjunction
Errors in mitosis or meiosis called nondisjunction.
Mitotic errors, after formation of zygote result in mosaicism.
Meiotic errors occur most frequently in meiosis I.
Meiosis I errors, gamete contains both paternal and maternal chromosomes.
Meiosis II errors, gamete with both copies of paternal or maternal chromosomes.
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a) Nondisjunction
at meiosis I
Nondisjunction
disomic
gametes
nullisomic
gametes Adapted from Gardner & Sutherland, Chrom. Abnl and Genetic Counseling
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b) Nondisjunction
at meiosis II
Adapted from Gardner & Sutherland, Chrom. Abnl and Genetic Counseling
disomic
gametes
Nondisjunction
nullisomic
gametes
normal gametes
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Nondisjunction
Nondisjunction can lead to:
Monosomy or one copy of a chromosome.
Trisomy or three copies of a chromosome.
Mosaicism or more than one cell line.
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Aneuploidy
Change in chromosome number that is not exact multiple of haploid set
Most spontaneously aborted.
Due to nondisjunction or failure of normal separation of chromosome pair (meiosis I) or chromatids (meiosis II) pre-fertilization.
Mosaicism-post fertilization.
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Polyploidy
Chromosome number is a multiple of the haploid number (23).
Euploid = 46 chromosomes
Triploid = 69 chromosomes
Tetraploid = 92 chromosomes
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Triploidy
69,XXY; 69,XXX; or 69,XYY
1-3% of all recognized pregnancies
15-20% of chromosomally abnl SAB.
<1/20,000 liveborns; survival days to few months
85% are diandric (2 paternal/1 maternal set of chromsomes)
15% are digynic (2 maternal/1 paternal set of chromosomes)
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Triploidy
Mechanisms
Haploid egg + 2 sperm = dispermy
Haploid egg + diploid sperm (MI or MII error)
Haploid sperm + diploid egg (failure to release polar body)
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Tetraploidy
92,XXXX or 92,XXYY
6-7% of spontaneous abortions
Due to replication without meiotic division
Less than 10 reported liveborns,
Survival in days
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Autosomal and Sex Chromosome Aneuploidy Syndromes
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Trisomy 21 (Down Syndrome)
Incidence: 1/700 (maternal age related)
Etiology: 90% maternal errors
75% MI 25% MII
3-5% paternal errors
Features: Mild to moderate mental retardation 30-40% risk of heart defects 1% risk for leukemia Alzheimer disease with age Male infertility
4% cases due to Robertsonian translocation
errors 2% mosaicism 94% trisomy 21
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Trisomy 18 (Edwards Syndrome)
Incidence: 1/7,500 (maternal age related)
Etiology: 90% maternal error
33% MI 66% MII
Features: Mental retardation Failure to thrive Neural tube defects Heart defects Short sternum Rocker bottom feet 2nd & 5th digits overlap 3rd & 4th Hypertonia
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Trisomy 13 (Patau syndrome)
Incidence: 1/15,000 (maternal age related)
Etiology: 70% maternal error
MI most common
Features: Mental and growth retardation Holoprosencephaly Cleft lip/Cleft palate Postaxial Polydactyly Clenched fists Rocker bottom feet Eye malformations Heart defects
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XXY (Klinefelter syndrome)
Incidence: 1/1,000 (maternal age related)
Etiology: 50% maternal errors
MI most common 50% paternal errors
Features: Tall, long, thin arms Gynecomastia Hypogonadism Infertility Germ cell tumors 15% mosaicism
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XXX
Incidence:
1/1,000 females (maternal
age related)
Etiology:
90% maternal errors
MI most common (75%)
Features:
Tall stature
Behavior problems
Risk of learning disabilities
Ovarian failure
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XYY
Incidence:
1/1,000 males
Etiology:
100% paternal error
MII most common
Features:
No abnormal features
Risk of learning disabilities
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45,X (Turner syndrome)
Incidence: 1/1,000 females 50% with 45,X 15% with structurally abnormal X 15% with mosaicism
Etiology: 80% missing paternal X
Features: Short stature Heart defect; coarctation of the aorta Cystic hygroma / Webbing of neck Gonadal dysgenesis Broad Chest Short 4th metacarpal Hand/Foot edema Renal abnormalities
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Structural Abnormalities of Chromosomes
Translocation
Insertion
Inversion
Deletion
Duplication
Derivative chromosome
Ring chromosome
Marker chromosome
Isochromosome
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Paracentric Inversion
E
Adapted from Elsevier Scientific
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Pericentric Inversion
Adapted from Elsevier Scientific
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Two chromosome breaks required.
Chromosome segment rotated 180 .
Usually no loss or gain of genetic material.
Occasionally break occurs in a gene or region critical for normal development or cellular regulation.
Two types: Paracentric
centromere outside of rotated segment
Pericentric centromere inside rotated segment
Inversions
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72 Ring
Insertion
Deletion Isochromosome
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46,XY,t(7;15)(p22;q22)
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Segregation of Reciprocal Translocations
Alternate
4
20 der(4)
der(20)
Normal
4
20
Balanced
der(4) der(20)
20 4
20
4
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Segregation of Reciprocal Translocations
Adjacent-1
Unbalanced
der(4) 20
4 der(20)
4
der(20) der(4)
20
4 20
20 4
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Segregation of Reciprocal Translocations
Adjacent-2
Unbalanced
4
der(4) 20
der(20)
20
der(20) der(4) 4
4 20
4 20
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Segregation Patterns in Metaphase I of Meiosis I
Alternate – gametes are normal or balanced and zygotes are viable
Adjacent-1 – gametes are unbalanced and zygotes maybe viable
Adjacent-2 – gametes are unbalanced and zygotes are presumably nonviable
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CHROMOSOME DELETION SYNDROMES
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Cri-du-Chat (Cry of the cat)
Deletion: 5p-5p15.2 critical region
Incidence: 1/20,000-1/50,000 1% of patients with IQ < 20 10-15% parental translocation
Features: Cat cry Micrognathia Low-set ears Microcephaly Hypotonia/Hypertonia Hypertelorism Mental retardation Heart defects
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Wolf-Hirschhorn Syndrome
Deletion: 4p-4p16.3 critical region
Incidence: 87% de novo 10-15% parental translocation
Features: IUGR Failure to thrive Microcephaly Greek helmet facies Cleft palate Heart defects Mental retardation Coloboma Seizures
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Greek Helmet
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MICRODELETION SYNDROMES
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Smith-Magenis Syndrome
Critical Region: 17p11.2
Incidence: 1/25,000
Features: Brachycephaly Prognathia Speech delay Mental retardation Growth Delay Behavior problems Hearing loss Scoliosis Heart defects Renal anomalies
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Prader-Willi Syndrome
Critical Region: 15q11.2-q13
Incidence: 1/10,000-1/15,000 70-80% paternal deletion
25% maternal uniparental disomy Imprinting mutation
Features: Hypotonia Mental retardation Short stature Food preoccupation w/ obesity Hyperphagia Hypogonadism Small hands and feet
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Angelman Syndrome
Critical Region: 15q11.2-q13
Incidence: 1/10,000 70% maternal deletion
5% paternal uniparental disomy 5% imprinting mutation 10% UBE3A mutation
Features: No speech Ataxia Mental retardation Seizures Microcephaly Inappropriate laughter Hypotonia Large mouth
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Williams Syndrome
Critical Region: 7p11.23 Elastin gene
Incidence: 1/20,000
Features: Mild mental retardation Periorbital fullness Supravalvular aortic stenosis Loquacious personality Anxiety Attention deficit disorder Hypercalcemia Stellate iris pattern
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VCF/DiGeorge Syndrome
Critical Region: 22q11.2
Incidence: 1/2,000-1/4,000 94% de novo
Features: Conotruncal heart defects Cerebral Palsy Learning disabilities Psychiatric illness Palate insufficiency Speech delay Nasal speech/tubular nose Long fingers Hypocalcemia Thymic aplasia/hypoplasia Parathyroid hypoplasia T-cell deficiency
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Miller Dieker Syndrome
Critical Region: 17p13.3
Features: Lissencephaly (smooth brain) Microcephaly Severe mental retardation Spasticity Seizures Vertical forehead furrows IUGR
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Fluorescence in situ hybridization (FISH)
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Initiated in 1990
“Southern on a glass slide” -non radioactive probes
Multiple probe types
Multiple tissue applications
FISH: Molecular Cytogenetics
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91 NIHGR
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• Centromere probes – Specific for given chromosome.
• Locus specific probes – Specific chromosome regions known to be
involved in genetic syndromes or cancers.
• Subtelomeric probes – Used to identify cryptic rearrangements in the
subtelomeric regions of chromosomes.
• Whole chromosome paints – Specific for chromosomes 1 through 22, plus
X,Y.
FISH Probes
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FISH on Tissues
Amniotic fluid / CVS
Non-neoplastic Tissue
Stimulated peripheral blood
Bone marrow or unstimulated PB cultured/uncultured, smears,
PET BM clot
Tumors- biopsy or tissue section Fresh, cultured, paraffin-embedded (formalin-fixed)
tissue
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Types of Probe Strategies
Dual/Triple color; dual fusion
Dual color; single fusion
Extra signal rearrangement
Break-apart rearrangement
Multi-color FISH
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Chromosome 9 Chromosome 22
ABL
gene BCR
gene
Arrows indicate
breakpoints
within the two
involved genes
Dual Color, Single Fusion
Dual Color, Extra Signal
Dual Color, Dual Fusion
VYSIS
FISH in CML
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BCR/ABL Probes
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Break-apart Strategy
Inv(16), MLL, MYC, EWS
Adapted from Vysis Website
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ETO/AML1 CBF split
D8Z2
Favorable prognosis
Intermediate prognosis
Unfavorable prognosis
t(8;21) inv(16)
MLL split
t(11;var)
(q23;var)
+8
D7S486/D7Z1
7q-
BCR/ABL
t(9;22) 5q-
EGR1/D5S23
t(15;17)
PML/RAR
Adapted from: Vance et al.
Leukemia Research, May 2007
Some FISH Probes for AML
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FISH Applications
Prenatal Lab
Detection of specific trisomies (13,18, 21) and numerical sex abnormalities (XY), follow with G-banding to confirm.
Leukocyte Lab
Detection of interstitial or terminal deletions (submicroscopic) or additional unknown material, and marker chromosomes.
Cancer Lab
Detect numerical and structural anomalies, diagnosis, remission, minimal residual disease, relapse, and transplant engraftment.
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Chromosomal rearrangements involving telomeres emerging as an important cause of human disease
~7% of unexplained MR have subtelomere rearrangements
50% of rearrangements are familial
Knight , Lancet 354:1676,1999
Subtelomere FISH
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101 Adapted from Korf:
Human Genetics
Subtelomere Probes
TTAGGG
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102 Adapted from Stohler, et al. AJMG, 2007
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Cancer Cytogenetics
An area of cytogenetics based on the identification or recurring abnormalities in malignant cells
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Conventional (G-banded) cytogenetic studies are utilized to:
Identify malignant disorders with specific chromosome abnormalities.
Assess the effectiveness of treatment.
Monitor remission.
Cancer Cytogenetics
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Modal Number
Diploid – 46 chromosomes
Hypodiploid – <44 chromosomes
Near Haploid – close to 23 chromosomes
Hyperdiploid – >46 chromosomes
High Hyperdiploid- >50 chromosomes
Pseudodiploid – 46 chromosomes with structural abnormalities
Numerical Abnormalities in Cancer
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Translocation
Insertion
Inversion
Deletion
Duplication
Isochromosome
Ring Chromosome
Marker Chromosome
Derivative Chromosome
Structural Abnormalities in Cancer
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t(X;18) – Synovial Sarcoma
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Chromosome Nomenclature
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A clone is defined as a cell population derived from a single progenitor. A clone exists if two or more cells containing the same structural abnormality or supernumerary marker chromosome.
OR
Three cells missing the same chromosome (ISCN, 2009, p.88).
Cytogenetic Definition of a Clone
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Frequently found as the sole karyotype abnormality and associated with a particular tumor. Ex: t(9;22)(q34;q11.2)
Primary Aberration (Stem Line)
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Rarely found alone; develops in cells already carrying a primary abnormality. Ex: t(9;22)(q34;q11.2),+8,i(17)(q10)
Secondary Aberration (Side Line)
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Chromosomal
Manifestations of Gene
Amplification
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Gene Amplification
• Importance:
– One mechanism for the activation of
cellular oncogenes.
– Reflects the genetic instability of the
tumor cell.
– Frequently characterizes aggressive
subsets of tumors.
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Gene Amplification (cont’d)
• Earliest, in vitro example of selective
(pressure) amplification was demonstrated
in mouse cells by Schimke in l978 with
amplification of the dihydrofolate reductase
gene (DHFR) conferring resistance to
methotrexate (MTX).
Cancer Genet & Cytogenet
1980; 2:339-348
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Gene Amplification (cont’d)
• Three “chromosome” structures associated
with amplification include:
– Homogenously staining region
(HSR)
• Integrated region of amplification
– Double minute chromosome (DM)
• Small, paired, acentric extra-
chromosomal body
– Episomes
• Submicroscopic extra-chromosomal
body
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Examples of Amplified Oncogenes
• MYCN (2p24) in neuroblastoma – Prototype for oncogene amplification in cancer.
– MYCN amplification also seen in retinoblastoma, small cell lung cancer, glioblastomas and astrocytomas.
– Amplified copies present as DM or HSR. • Amplicons usually range from 100-200 kb. • Proportion of tumors with amplified MYCN, ~20%. • Usually associated with a poor prognosis.
• ERBB2/HER2 (17q21) in breast cancer
– First observed in breast cancer cell line MAC117.
– Observed in ~18-20% of primary breast tumors.
– Amplification correlated with decreased overall survival
and time to relapse.
– Specific therapy, trastuzumab (Herceptin),
lapatinib/capecitabine, pertuzumab.
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HER2 Testing by FISH
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First identified in 2003 during routine screening by FISH with ETV6/RUNX1 probe set.
In karyotype, often associated with an additional marker or ring chromosome.
Observed in both adult and pediatric patients.
Incidence estimated at 1.5-2.0% of childhood ALL
Associated with poor prognosis
Amplification of RUNX1 in ALL
Adapted from Leukemia
2003;17:547-553
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t(12;21) [VYSIS]
Amplified RUNX1 on Marker
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ABL1 Amplification in T-Cell ALL
• First reported in 2004 by C. Graux, et al*.
– “Fusion of NUP214 and ABL1 on amplified
episomes in T-cell acute lymphoblastic leukemia”
– Screened for possible ABL1
rearrangements in CML by FISH. • 5/90 (5.6%) had extrachromosomal amplification (>10
copies) of ABL1.
• Amplification was extrachromosomal but not
observed by G-banding (episomes).
• FISH mapping confirmed amplification of ABL1,
LAMC3, and NUP214 (CAN) localized to 500-kb region
on 9q34.
* Nature Genetics 2004, 36:1084-89.
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Leukemia
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Myeloid leukemias
CML and pre-B-ALL t(9;22)(q34;q11.2) BCR/ABL1
AML-M2 t(8;21)(q22;q22) CBFA2T1/RUNX1
AML-M2 t(7;11)(p15;p15) HOXA9/NUP98
AML-M3 t(15;17)(q24;q21.1) PML/RARA
AML-M3, atypical t(5;17)(q35;q21.1) NPM1/RARA
AML-M3, atypical t(11;17)(q23;q21.1) PLZF/RARA
AML-M3, atypical t(11;17)(q13;q21.1) NuMA1/RARA
AML-M3, atypical t(17;17)(q11.2;q21) STAT5B/RARA
AML-M4eo inv(16)(p13.1;q22) MYH11/CBFB
CMML t(5;12)(q33;p13) PDGFRB/ETV6
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B cell leukemias and lymphomas
precursor-B ALL t(12;21)(p13;q22) ETV6/RUNX1
precursor-B ALL t(1;19)(q23;p13.3) PBX1/TCF3
Burkitt lymphoma t(8;14)(q24;q32.3) MYC/IGH@
Burkitt lymphoma t(2;8)(p12;q24) IGK@/MYC
Burkitt lymphoma t(8;22)(q24;q11.2) MYC/IGL@
Mantle cell lymphoma t(11;14)(q13;q32.3) CCND1/IGH@
Follicular lymphoma t(14;18)(q32.3;q21) IGH@/BCL2
Diffuse large B cell lymphoma t(3;14)(q27;q32.3) BCL6/IGH@
Lymphoplasmacytic lymphoma t(9;14)(p13;q32.3) PAX5/IGH@
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T cell leukemias/ lymphomas
T-ALL
7p14-15
7q35
14q11.2
TRG@
TRB@
TRA/B@
T-ALL
t(7;11)(q35;p13)
TRB@/LMO2
ALCL
t(2;5)(p23;q35)
ALK/NPM1
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World Health Organization (WHO) Classification for Leukemias 2001 Acute myeloid leukemia with recurrent cytogenetic
abnormalities – AML with t(8;21)(q22;q22) (AML1/ETO) AML with inv(16)(p13.1q22) (CBFB/MYH11) APL with t(15;17)(q22;q21.1) (PML/RARA) AML with 11q23 (MLL) abnormalities
Subtypes of Acute Leukemia
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New Subtypes of AML WHO Classification 2008
AML with recurrent genetic abnormalities AML with t(8;21)(q22;q22)(RUNX1/RUNX1T1)
AML with inv(16)(p13.1q22)(CBFB/MYH11)or t(16;16)(p13.1;q22)
AML with t(15;17)(q22;q21.1)(PML/RARA)
AML with t(9;11)(p22;q23)(MLLT3/MLL)
AML with t(6;9)(p23;q34)(DEK/NUP214)
AML with inv(3)(q21q26.2(RPN1/MECOM(EVI1)or t(3;3)(q21;q26.2)
AML with t(1;22)(p13;q13)(RBM15/MKL1)
AML with mutated NPM1
AML with mutated CEBPA
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t(8;21)(q22;q22.3)
RUNX1T1 (ETO)/RUNX1 (AML1)
5-12% cases AML (M2)
Loss of a sex chromosome
AML
• t(15;17)(q24;q21.1)
PML/RARA
– 5-8% of AML (M3)
– Disseminated
intravascular
coagulation
– STAT FISH test
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Chromosome 16 Abnormalities
inv(16)(p13.1q22) and t(16;16)(p13.1;q22)
Generally classified as acute myelomonocytic leukemia
(AML-M4) with bone marrow eosinophilia (AML-M4Eo) FAB or
Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13.1q22) and t(16;16)(p13.1;q22) by WHO classification
Inv(16) and t(16;16) account for approximately 10-12% of AML
Genes involved-MYH11 at 16p13.1 (Smooth muscle myosin heavy chain gene)and CBFB (Core binding factor beta) at 16q22
Creates a transcriptionally active fusion gene
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Chromosome 16 Abnormalities
del(16)(q22)
Patients may present with MDS and then transform to AML
Less frequent than inv(16) and t(16;16)
Patients have loss of genes on 16q (LOH mechanism for leukemogenesis)
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Mixed Lineage Leukemia • MLL - 11q23 involved with multiple translocation
partners
– Accounts for 5-6% of cases.
– Seen in infant leukemia and secondary
leukemia with topoisomerase inhibitors.
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2
1
3
5
6 7
8 9 10
11
12
13 14 15
16
17 18
19 20 21 22
Y
X
1p32
4q21 5q12
5q31 9q34
6q27
1q21
3p21
1q32
3q25
3q28
9p22
10p11.2
10p13
11q23
14q24
15q15
16p13
17q25
17q21 17q23
19p11 19p12 19p13
22q11.2
2p21
Xq13
12q13
Chromosomal partners for 11q23
Adapted from www.pathology.washington.edu
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ALL Metaphase
Acute Lymphoblastic Leukemia
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Acute Lymphoblastic Leukemia
Adult ALL – 5 year survival is approximately 40%
Childhood ALL- 5 year survival 75-80%
ALL accounts for 75-80% of childhood leukemia; less common in adults
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Hyperdiploidy
>50 chromosomes, account for 25% of total cases.
Frequently see gains of X, 4, 6, 10, 14, 17, 18, and 21.
t(12;21)(p13;q22) ETV6/RUNX1
Accounts for 22% of cases.
Has a favorable prognosis
T cell-ALL
Accounts for ~12% of cases.
Has an intermediate prognosis.
MLL(11q23)
Accounts for 8% of cases
ALL t(9;22)
Account for 3% of cases
Worst prognostic
group-however
changing with TKIs
for 9;22
ALL Classifications in Children
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High Hyperdiploid Karyogram
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t(12;21) [VYSIS]
RRGF
t(12;21)(p13;q22)
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der(19)t(1;19)(q23;p13.3) Pre-B ALL
PBX1/TCF3
20% ALL with pre-B phenotype
~6% of childhood ALL
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Hypodiploid ALL 43 or fewer chromosomes
Rare, ~3% of patients with ALL
Subgroups
Near haploid 24-31 chromosomes
Low hypodiploid 32-43 chromosomes
Associated with a poor prognosis
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Infant Leukemia Leukemias diagnosed in the first 12-months of life.
May be lymphoid or myeloid.
Accounts for 2.5-5% of ALL and 6-14% of pediatric AML.
Infant ALL associated with rearrangement of MLL gene,11q23
Most common karyotype for ALL is t(4;11)(q21;q23) (AFF1(AF4)/MLL).
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MLL [VYSIS]
NORMAL BCR/ABL1/ASS [VYSIS]
NORMAL
ALL Panel
t(12;21) [VYSIS]
NORMAL
CEP 4(SO), CEP 10 (SG)
CEP 17(SA) [VYSIS]
NORMAL
ALL Panel
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Burkitt Lymphoma
FAB L3 morphology
Classification: 1) Endemic; 2)Sporadic;
3)Immunodeficiency-associated
Chromosome translocations lead to deregulation
of MYC oncogene
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Burkitt Lymphoma
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Breakpoints on chromosome 8 are 3’ and breaks on chromosome 2 and 22 occur 5’ of the Kappa and Lambda gene constant region segments.
Light chains move to chromosome 8.
Variant Translocations
Atlas of Cancer Cytogenetics
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FISH for Burkitt Lymphoma
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Multiple Myeloma Cytogenetics
16-20% t(11;14)(q13;q32) CCND1/IGH@
15% t(4;14)(p16.3;q32) FGFR3-WHSC1/IGH@
4% t(6;14)(p21;q32) CCND3/IGH@
5-8% t(14;16)(q32;q22) IGH@/MAF
t(16;22)(q22;q11.2) MAF/IGL@
45% hyperdiploid 3,5,7,9,11,15,19,21
Blood 109, 31:32-3133,
2007
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t(11;14) [VYSIS]
NORMAL
RB1(SG), CEP12(SO) [VYSIS]
NORMAL D13S319 [VYSIS]
NORMAL
FISH Panel for Multiple Myeloma
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Comparative Genomic Hybridization (CGH)
Analyzes gains and losses of genetic material (unbalanced abnormalities).
May be performed on metaphases or on spotted DNA/RNA (arrays).
Total test DNA is labeled with one color, normal “competing” DNA with a second color.
The two DNAs are mixed and hybridized to normal metaphase cells or normal DNA on a spotted array.
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Courtesy of Signature Genomics
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CGH Metaphase
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Composite of CGH Metaphase
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156 Courtesy of Signature Genomics
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157 Courtesy of Signature Genomics
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158 Courtesy of Signature Genomics
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159 Courtesy of Signature Genomics
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Oligo-Based CGH Arrays
Greater density of probes
Greater coverage
No dye-reversal or mismatch of sex for control DNA
Multi-plexed
Filters set
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Targeted Array CGH Diagnostic Applications
Microscopic chromosome abnormalities Aneuploidy (mosaicism)
Unbalanced translocations
Chromosomal origin of centric and noncentric markers.
Submicroscopic alterations Microdeletions
Microduplications
Unbalanced subtelomeric rearrangements (del, der)
Will not detect balanced alterations (rcp, inv, rob, ins)
ACMG Practice Guidelines-Genet Med 2010:12(11):742-745
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SNP Arrays
• Single nucleotide polymorphisms (SNP) -DNA sequence variations in which a single nucleotide differs on paired chromosomes (or between individuals).
• Specialized software aligns SNPs in chromosomal order.
• Single test DNA is labeled and hybridized to the array.
• SNP-based arrays quantitatively determine copy number (gains/losses), but compare result to a historic reference control.
• Capable of detecting allelic copy neutral changes such as loss of heterozygosity (LOH) and Uniparental disomy - segment or entire chromosome from one parent is missing and replaced by gain of the other.
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del(13)(q14.1q31.2) (46 Mb)
B-allele frequency
Log R ratio
←no het→
decreased intensity
BB
AB
AA
Courtesy of T. Smolarek CCHMC 165
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Copy Number Variations
• DNA segment (>1 kb) with a variable copy number compared to normal reference genome.
• Occur on every chromosome; cover ~12% of genome.
• Complicates the interpretation of microarray data.
• Determine if CNV is pathogenic or benign
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Copy Number Variants Guidelines
Pathogenic Benign
Inherited from an affected parent Inherited from a healthy parent
Similar CNV in affected relative Similar CNV in healthy relative
Gene-rich area Gene-poor area
Expanded or altered CNV from affected parent
Completely contained within genome imbalance
Identified in database as pathogenic Identified in database as probably benign
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Copy Number Variant Resources
• Databases
– DECIPHER- http://decipher.sanger.ac.uk/
– Database of Genomic Variants- http://projects.tcag.ca/variation/
• Pub Med
• OMIM
• UCSC Browser
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Summary of Cytogenetic Resolution
• Karyotyping ~5-10 Mb of DNA
• FISH ~50-200 kb of DNA
• Multicolor FISH ~ 5- 10 Mb of DNA
• Metaphase CGH ~ 5-10 Mb of DNA
• aCGH –BAC platform ~200 kb of DNA
• aCGH –Oligonucleotide array ~50 kb of DNA
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Association for Molecular Pathology 9650 Rockville Pike
Bethesda, MD 20814
www.amp.org
© Association for Molecular Pathology, 2013 170