Cancer Cytogenetics I - Chromosomal Abnormalities in Leukemia Flashcards
Speed of progression
acute or chronic
Types of cells affected
lymphoid or myeloid
Rapidly growing leukemia (AML/ALL)
immature blood cells, they cannot carry out their normal blood functions, grow rapidly, rapidly progressive disease, acute leukemia requires aggressive treatment
Slow-progressive leukemia (CML/CLL)
Mature cells are related with disease, abnormal cells are accumulated until that is enough to cause disease, sometimes it takes several decades to cause symptoms, many cases are found during general physical exam
Risk for most leukemias increase with
age
The median age of a patient diagnosed with AML, CLL, or CML is
65 or older
When blast cells are detected at 20% or greater in bone marrow, then _____ _____ is present
acute leukemia
acute leukemia is caused by
immature cells failing to mature
What causes chronic leukemia
abnormal cells mature partially, but disease occurs because the abnormal cells never die
t(9;22) is associated with
CML, ALL, AML
t(8;21), inv(16), and t(15;17) is associated with
AML
what is the prognosis of 13q deletion
good prognosis
what is the prognosis of 17p deletion
poor prognosis
What is the benefit of recurrent chromosomal abnormalities analysis in leukemia?
diagnosis, prognosis, monitoring disease progression, and targeted therapy
Targeted therapy for t(9;22)
imatinib
Targeted therapy for t(15;17)
ATRA (all-transretinoic acid) and arsenic
Targeted therapy for inv(16)
cytarabine
Types of chromosomal abnormalities in cancer
copy number loss (monosomy), copy number gain (trisomy), deletion, inversion, duplication, isochromosome
Copy number loss associated with
lower expression, higher risk for disease expression
Copy number gain associated with
overexpression
Translocation associated with
at least two chromosomes involved
Nomenclature for balanced translocation
“t” stands for balanced translocation, in balanced translocation the smaller chromosome # is listed first
Nomenclature for unbalanced translocation
“der” stands for derivative chromosomes, the chromosome with a centromere is referenced first
deletion associated with
only one chromosome involved
What are the two types of deletions
terminal and interstitial
terminal deletion
one breakpoint
interstitial deletion
two breakpoints
Nomenclature of deletions
use “del”, breakpoint nearest to centromere is listed first
inversion associated with
Only one chromosome involved
what are the two types of inversions
pericentric and paracentric inversion
Paracentric inversion
does not include the centromere, and both breaks occur in one arm of the chromosome
Pericentric inversion
includes the centromere and there is a break point in each arm
Nomenclature for inversions
use “inv”, pericentric inversions are described from p to q; paracentric is described by whichever is closest to the centromere
duplication associated with
one chromosome involved
Nomenclature for duplication
use “dup”
Isochromosome
mirror image chromosomes that arise when one part of the chromosome is duplicated and separated from the other).
Monocentric isochromosomes
when the breakpoint occurs within the centromere (due to centromere misdivision or centric fission)
Dicentric isochromosomes
occurs when the chromosomal break maps outside of the chromosome and results in two centromeres. Unstable unless one of the centromeres becomes inactivated.
How many cells are needed to define clonal copy number loss (monosomy)?
Minimum of three metaphase cells with the same chromosome loss
How many cells are needed to define clonal copy number gain (trisomy, tetrasomy)?
Minimum of two metaphase cells with the same chromosome loss
How many cells are needed to define clonal structural abnormalities?
Minimum of two metaphase cells with the same chromosomal abnormality
Limitations of chromosome analysis and use of FISH panel for leukemia diagnosis
low cell count after chemotherapy, slow growing cells in CLL, G0 arrest in CLL, low cell population in bone marrow, inv(16) & inv(3), small amounts of cells (dry tap) or bone marrow unavailable, culture is impossible, subtle changes (such as 4q12 rearrangement in eosinophilia)
Primary event that causes CML
t(9;22) with BCR::ABL1 fusion/rearrangement has been seen in 90-95% patients with CML. This is called the philadelphia chromosome.
ABL1 gene normal function
It is a protooncogene that functions as a non-receptor tyrosine kinase.
When 5’BCR and 3’ABL1 are fused, the tyrosine kinase domain is constitutively activated in results in
increased cell proliferation, inhibits apoptosis, increases invasiveness, inhibits DNA repair, and finally causes CML
CML is a triphasic disease, what are the three phases?
The chronic phase, the accelerated phase, and the blast-phase (acute leukemia)
The chronic phase (CP) of CML is associated with
less than 10% blast cells, this phase can last for several years with no symptoms or mild symptoms, the t(9,22) is usually the only chromosomal anomaly
The accelerated phase (AP) of CML is associated with
<15% blast in bone marrow or blood, patients become progressively impaired and develops new cytogenetic changes outside of the philadelphia chromosome
The blast-phase (BP) of CML is associated with
> 30% blasts in the blood or bone marrow, it is difficult to control and usually there are many additional chromosomal abnormalities. Typically see philadelphia chromosome (Ph+), i(17q), +19, -Y, +21, +17, and monosomy 7
Chromosomal abnormalities seen in acute lymphoid leukemia (ALL)
t(9;22), t(12;21), hyperdiploidy, KMT2A rearrangement, iAMP (intrachromosomal amplification of chromosome 21)
Which test should be performed in pediatric/young adult cases of b-lineage ALL?
g-banded chromosome analysis should be performed simultaneously with interphase FISH analysis that includes the following probes: t(9;22), KMT2A rearrangement, t(12;21), and hyperdiploidy
Which chromosomal abnormalities in ALL is associated with poor prognoses?
t(9;22) and KMT2A rearrangement
Which chromosomal abnormalities in ALL is associated with good prognoses?
t(12;21), hyperdiploidy
What is one of the most common non-random, recurrent translocation associated with childhood ALL?
t(12;21)(p13.2;q22.12) with ETV6::RUNX1, favorable prognosis
chromosomal abnormalities associated with AML
t(8;21) with RUNX1::RUNX1T1, inv(16) and t(16;16) with CBFB::MYH11, t(15;17) with PML::RARA, and inv(3) and t(3;3) with RPN1::MECOM
t(8;21) subtype of AML
its detection alone establishes the diagnosis of AML regardless of blast cell count, found in 5-10% of AML, most cases occur as a sole chromosomal change, RUNX1::RUNXT1 fusion gene product acts in a dominant negative fashion; FAVORABLE PROGNOSIS
Inv(16)/t(16;16) with CBFB::MYH11 subtype of AML
its detection alone establishes a diagnosis of AML regardless of blast cell count, found in 5-10% of AML, inversion is more common (95%) than the translocation (5%), CBFB::MYH11 fusion gene prevents normal heterodimer formation (dominant negative effect), FAVORABLE PROGNOSIS
Core-binding factor leukemias (CBFLs) - t(8;21) and inv(16)/t(16;16)
presence of t(8;21) with RUNX1::RUNX1T1 or inv(16)/t(16;16) with CBFB:MYH11 are defined as core-binding factor leukemias. CBF-AML have a shortage of all types of mature blood cells and usually begins in young childhood. FAVORABLE PROGNOSIS
Inv(3)(q21q26.2)/t(3;3)(q21;q26) AML subtype
detected in about 1-2% of AML, inv(3) more common than t(3;3), strongly associated with multilineage dysplasia, POOR PROGNOSIS
chronic lymphoid leukemia
disorder related to disruption of apoptosis of monoclonal b-lymphocyte cells
chromosomal abnormalities associated with CLL
11q-, trisomy 12, 13q-, 17p-
CLL overview
most common leukemia in adults, slow progress, most people are asymptomatic for years, overtime the cells metastasize to lymph nodes, liver, and spleen
Gene associated with deletion of 11q
ATM
Gene associated with deletion of 17p
TP53
