Molecular/Cytogenetic Testing in Myeloid Neoplasia Flashcards
(31 cards)
What is the advantage of RNA-based testing ?
- does not require amplification of large intronic regions
What role do molecular assays play in
myeloid neoplasm testing ?
- detection of mutations
- RNA-based PCR can detect gene fusions (ex BCR-ABL1)
- can detect mutation resistance and MRD monitoring
What is a common mutation seen in
CML that makes it resistant to treatment with a TKI ?
- ABL1 p.T315I
What is the basis of clonal hematopoieis of
indeterminate potential (CHIP) ?
- this is an age related phenomenon
- it is a clonal hematopoiesis in the bone marrow compartment that is not associated with cytopenias or known hematopoietic neoplasms
- occurs in the older population
- humans acquire 14 somatic mutations per year of life
- most are in non-coding regions
- coding somatic mutations increase with age
What risks are seen with CHIP ?
- carries an increased risk of cardiovascular disease (more so than even some known CV risk factors)
- associated with low-risk of progression to future hematolymphoid neoplasm (0.5%-1% per year) in a healthy individual
- if CHIP present in patient receiving myelotoxic therapy or undergoing BMT
- 4x the risk of therapy related myeloid neoplasm
- expansion of clone with acquired additional mutations
What types of genes are involved
in Chronic myeloid neoplasms, precursors states
CHIP and CCUS ?
- many of the genes are drivers in myeloid neoplasma, including TP53
- Categories of Genes
- Cohesin
- Epigenetics
- Signaling
- Splicing
- Transcription
- Other
What genes are considered
cohesin genes?
- RAD21
- SMC3
- STAG2
- Other Cohesin1
What genes are considered
Epigenetic?
- ASXL1
- BCOR
- BCORL1
- DNMT3A
- EZH2
- IDH1
- IDH1/2
- IDH2
- TET2
What genes are considered to
be part of signaling ?
- CALR
- CBL
- CSF3R
- FLT3
- JAK2
- KIT
- KRAS
- MPL
- NF1
- NRAS
- PTPN11
What genes are considered to be
Splicing ?
- SF3B1
- SRSF2
- U2AF1
- ZRSR2
What genes are considered to be
Transcription factor associated ?
- CEBPA
- ETV6
- PHF6
- PPM1D
- RUNX1
- SETBP1
What are considered to be
other genes ?
- TP53
- NPM1
What malignancies can CHIP
genes be seen in?
- myeloid and lymphoid cellular compartments
- can be mutations or cytogenetic aberrations inlcuidng copy number alterations
What is the typical VAF
for CHIP ?
- VAF = 2-10%
- generally low-level of involvement
- single aberrations can wax and wane over time
What is clonal cytopenia of
uncertain significance (CCUS)?
- similar alterations CHIP
- but these cases fail to meet diagnostic criteria for MDS etc
- in the presence of unexplained cytopenia the presence of certain mutations and mutation patterns there is significant progression to a neoplasm
- number of mutations (>2)
- VAF of the mutations ( >8%)
- specific genes that are mutated
- IMP: risk of progression with each mutation, 2 or more genes carry 88% positive predictive value for myeloid neoplasm
Which genes in CCUS are considered
high risk for progression to neoplasm ?
- epigenetic
- spliceosome
- RUNX1
- JAK2
IMP:
up to 10% per year risk of progression with high risk patterns and high risk CCUS genes.
Which group of patients do high risk
CCUS patients have a similar overall
survival to ?
- low-risk MDS (no blasts)
- both are similar functionally
The presence of which cytogenetic
abnormalities allow for a presumptive
diagnosis of MDS in the absence of dysplasia ?
- del 5q
- del 7/7q
- del 11q
IMP: remember many cytogenetic aberrations can be seen in multiple myeloid neoplasms even at low levels and cannot be used to diagnose MDS. Also, seen during cytotoxic therapy and resolve after therapy
- ex: trisomy 8, del 20q, deletion Y
- careful with clones of <35% of metaphases with aberrations
What is the recommendation for evaluation
of MDS cytogenetics ?
- Karyotype with metaphase analysis is the preferred method
- especially since the changes in MDS are so complex
- FISH
- recommended only in the failure to obtain 20 evaluable metaphases
How many genes are implicated
in MDS?
- up to 47 different genes are recurrently mutated
- no particular mutational pattern is associated with any single subcategory of MDS, except SF3B1
- with disease progression additional mutations are acquired
- result of mutliple subclone events
- the more mutations the worse the prognosis
Which cytogenetic events are NOT
MDS defining ?
- trisomy 8
- del 20q
- loss of Y
Which cytogenetic abnormality
in MDS confers sensitivity to Lenalidomide ?
- del 5q
What malignancies other than
CML can the BCR-ABL fusion be identified in ?
- AML
- B-ALL
- mixed-phenotype AML (MPAL)
What are the breakpoints of BCR-ABL
in CML ?
- intronic breakpoints lead to the gene fusion
- BCR exons denoted as e
- ABL exons denoted as a2
- most common in CML: p210 (e13a2 or e14a2)
- minor p190 in CML (more common in pediatric B-ALL)
- e1a2
- p230 is a rare variant (e19a2)
