Flashcards in 10/29 - Gollin's Class: Nonrandom Chromosomal Abnormalities in Cancer Deck (38)
Boveri suggested what?
that malignant tumors arise from a single cell that has acquired an abnormal chromosome constitution
Splitting or increased expression of NuMA may cause what?
formation of new spindle poles
Is cancer a genetic disease?
- Yes and no
- A very small percentage of cancers are "genetic" (hereditary)
- Most cases are not familial, but due to acquired changes in genes in a somatic cell, but not in a germ cell.. So can't be passed onto the next generation
Cancer is a disease in which there is...
Too much cell proliferation and too little cell death
Growth-related genes that play a role in cell proliferation. Can think of these as the accelerator pedal on a car and sometimes it can get stuck, leading to cell proliferation.
Tumor Suppressor Genes
Regulators of cell proliferation; like brakes on a car.
DNA repair genes
- Genes that repair the mistakes made when the DNA is copied or altered by chemicals or radiation
- These are like the repair technician for the car.
- If he/she isn't available, and something in the car breaks down, the car may still drive, but could become more damaged as it drives along
The DNA repair genes must be working so that....
- Defective or damaged DNA doesn't get replicated, leading to more and more defective cells and more defects in the genes, some of which may cause defects in cancer-related genes, creating cells with more and more defects, perhaps making them resistant to therapies, the condition that actually kills the patient
Genomic changes in cancer
- can involve large chromosomal duplications, deletions or translocations or smaller submicroscopic deletions or duplications or even single base pair mutations
History of Cancer Cytogenetics
1902: Theodor Boveri - chromosome/spindle abnormalities in cancer
1960: Peter Nowell - Philadelphia chromosome in CML
1970: Janet Rowley - Philadelphia chromosome results from the t(9;22)(q34;q11.2) translocation
1982: the t(9;22) involves transfer of the ABL1 oncogene to the BCR on 22q, resulting in abnormal tyrosine kinase activity (successfully used to formulate the first targeted therapy for CML)
Chronic Myeloid Leukemia (CML)
- CML (Proliferative disorder of hematopoietic stem cells)
- Philadelphia (Ph) chromosome: unique chromosome abnormality)
- BCR-ABL1 tyrosine kinase: A single molecular abnormality that causes transformation of a hematopoietic progenitor into a malignant clone.
Clinical Course: Phases of CML
- Chronic phase (median 5-6 years stabilization)
- Accelerated phase (median duration 6-9 months)
- Blast crisis (median survival 3-6 months)
25-40% of CML patients progress directly from what stage to what stage?
Directly from chronic phase to blast crisis without evidence of a transitional accelerated phase
Chronic Phase of CML
- There are less than 10% blasts i peripheral blood and bone marrow, and the white blood cell (WBC) count at presentation is typically elevated
Accelerated Phase of CML
- There are more than 10 - 15% (but less than 30%) blasts in either peripheral blood or bone marrow. Symptoms may increase and include unexplained fever, bone pain, splenomegaly, and hepatomegaly.
Blast crisis phase of CML
- There are more than 30% blasts in peripheral blood or bone marrow and symptomatology is increased especially relating to anemia and infection, CNS disease, lymphadenopathy and bleeding.
- This phase is rapidly fatal
- The first tyrosine kinase inhibitor commercially available for clinical use
- Selectively blocks cellular proliferation and induces apoptosis in Ph chromosome-positive cells harboring the BCR-ABL1 tyrosine kinase, the causative abnormality in CML
- Also targets the tyrosine kinase activity of the receptors for platelet-derived growth factor, stem cell factor, and KIT, and inhibits PDGF- and SCF- mediated cellular events
Rationale for use of Gleevac in CML
- CML is characterized by a t(9;22) translocation known as the Ph chromosome
- The product of this fusion gene is the BCR-ABL1 tyrosine kinase, which is thought to be leukemogenic
- Gleevec is an inhibitor of BCR-ABL1 kinase
- Inhibition of BCR-ABL1 kinase should be an effective therapy for CML
- Gleevec shows anti-cancer activity in CML patients and other cancer patients (GIST)
Chromosomal Alterations in Cancer
- Specific chromosome changes have been identified in many leukemias, lymphomas, sarcomas, carcinomas, and virtually all cancers
- The breakpoints have been cloned to identify many genes involved in the development and progression of these cancers
- Hundreds of gene fusions have been identified in tumors
Indications for Bone Marrow Chromosome Analysis
- At initial aspirate, when hematologic malignancy is suspected, for classification, prognosis and choice of treatment
- At follow-up aspirate after treatment, to verify remission
- At relapse of leukemia/lymphoma, for characterization of karyotipic evolution
- Prior to bone marrow transplant to establish patient's chromosomal abnormalities
- After bone marrow transplant, to (1) document engraftment and (2) for early diagnosis of relapse or secondary leukemia
Chromosomal abnormality specifics in CML, ALL
Chromosomal abnormality specifics in AML
Chromosomal abnormality specifics in APL
Chromosomal abnormality specifics in AML with EO
Chromosomal abnormality specifics in MDS/AML
Chromosomal abnormality specifics in CLL
Chromosomal abnormality specifics in ALL
Chromosomal abnormality specifics in Burkitt Lymphoma
Chromosomal abnormality specifics in Follicular Lymphoma