Cancer Cytogenetics - GO THROUGH END AGAIN Flashcards
which techniques are used for both constitutional and cancer cytogenetics?
- karyotype
- FISH
- chromosome microarray analysis (CMA)
CMA compared to karyotyping and fish
- used less frequently to analyze cancer specimens
numerical abnormalities
- chromosomal abnormalities that change the number of chromosomes
structural abnormalities
- chromosomal abnormalities that change the structure of the chromosome
chromosome abnormalities cause disease by
- altering concentration of particular gene products
- altering gene product
ways to alter concentration of particular gene products
- duplication or amplification
- deletion or gene interruption
what kind of genes are typically duplicated or amplified in cancer
- oncogenes
what kind of genes are typically deleted or disrupted in cancer?
- tumor suppressor genes
how does cancer alter the gene product?
- produces a few fusion gene with altered expression
- new fusion protein with altered function
CML accounts for what percent of leukemia
15-20%
CML occurs most frequently in what age group
40-50
importance of CML
- first cancer to be associated with a specific recurrent chromosome abnormality
chromosome problems in CML
- Ph chromosome secondary to a (9;22) translocation
the Philadelphia chromosome contains a
- fusion gene composed of BCR serine/threonine on 22 and ABL1 tyrosine kinase on 9
the new fusion BCR/ABL1 tyrosine kinase produced by the fusion gene
- permanently turned-on
- activates a number of signaling pathways
permanent activation of BCR/ABL1 fusion kinase leads to
- malignant transformation
- by interfering with basic cellular processes
what process is used to identify that BCR/ABL1 fusion gene
- FISH
what do you see on FISH in BCR/ABL1 fusion
- yellow fusion signal on part of 9 and part of 22
BCR/ABL1 fusion tyrosine kinase as a target for what kind of drug therapy
- tyrosine kinase inhibitors
Imatinib (Gleevec) MOA
- tyrosine kinase inhibitor
- blocks ATP binding center of BCR/ABL1 kinase which blocks phosphorylation of various proteins that contribute to cell signaling and uncontrolled growth
results of imatinib
- induces long lasting remissions and is well tolerated
complete cytogenetic response rate for newly diagnosed CML patients in chronic phase
- 70-98%
estimated 3 year survival rate for newly diagnosed CML in chronic phase
- 94%
what do we do for patients with early blast phase with first line TKI
- bone marrow/stem cell transplantation
- only cure for CML
chromosome abnormalities involved MLL has been implicated in what percent of acute leukemias
- 10% of AML and ALL
chromosome abnormalities in acute leukemia located where
- 11q23.3
- KMT2A gene
11q23.3 encodes
- transcriptional regulatory factor essential for embryonic body plan formation and self-renewal of hematopoietic stem cells and immature progenitors
what is the prognosis for 11q.23.3 abnormalities
- generally associated with poor prognosis
therapies for patients with MLL rearrangements
- no targeted therapies
recurrent MLL translocations associated with how many partner genes
- 80
mechanism whereby the multiple MLL fusion partners initiate cellular transformation
- largely unknown
fusion protein in MLL acts as what kind of mutation
- dominant gain of function
what do you see in G-banding karytope of MLL
- short 4 chromosome
- long 11 chromosome
what will microarray testing not detect
- balanced rearrangements
- low level mosaicism
balanced rearrangements
- no gain or loss present to identify the rearrangements
when do we see low level mosaicism/clonal evolution
- minimal residue disease
- data from normal cells masks data from abnormal cells
minor clones that provide information about disease progression - in microarray testing
- may be difficult to detect
what percentage of abnormalities detected in cells are not detected by CMA?
- abnormalities present in less than 10-15% of cells
what are some of the cytogenetic abnormalities missed by traditional cytogenetic testing that microarray can detect
- cryptic rearrangements below level of G-band detection
- those without FISH probes
- copy number neutral loss of heterozygosity or acquired homozygosity
what is a big problem that karyotyping has
- resolution problems
what has been identified as a major mechanism of tumor suppressor gene inactivation
- copy number neutral loss of heterozygosity
- acquired homozygosity
what technique is required for loss of heterozygosity
- SNP microarray
copy number neutral loss of heterozygosity or acquired homozygosity is a common finding in
- all types of leukemia
monitoring for cancer is typically done by what cytogenetic techniques
- karyotyping
- FISH
what condition has a very specific rearrangement
- CML
what condition has a rearrangement that involves multiple partners
- MLL
