10/29 - Gollin's Class: Nonrandom Chromosomal Abnormalities in Cancer Flashcards

1
Q

Boveri suggested what?

A

that malignant tumors arise from a single cell that has acquired an abnormal chromosome constitution

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2
Q

Splitting or increased expression of NuMA may cause what?

A

formation of new spindle poles

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3
Q

Is cancer a genetic disease?

A
  • 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
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4
Q

Cancer is a disease in which there is…

A

Too much cell proliferation and too little cell death

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5
Q

Oncogenes

A

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.

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6
Q

Tumor Suppressor Genes

A

Regulators of cell proliferation; like brakes on a car.

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7
Q

DNA repair genes

A
  • 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
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8
Q

The DNA repair genes must be working so that….

A
  • 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
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9
Q

Genomic changes in cancer

A
  • can involve large chromosomal duplications, deletions or translocations or smaller submicroscopic deletions or duplications or even single base pair mutations
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10
Q

History of Cancer Cytogenetics

A

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)

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11
Q

Chronic Myeloid Leukemia (CML)

A
  • 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.
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12
Q

Clinical Course: Phases of CML

A
  • Chronic phase (median 5-6 years stabilization)
    ADVANCED PHASES:
  • Accelerated phase (median duration 6-9 months)
  • Blast crisis (median survival 3-6 months)
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13
Q

25-40% of CML patients progress directly from what stage to what stage?

A

Directly from chronic phase to blast crisis without evidence of a transitional accelerated phase

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14
Q

Chronic Phase of CML

A
  • There are less than 10% blasts i peripheral blood and bone marrow, and the white blood cell (WBC) count at presentation is typically elevated
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15
Q

Accelerated Phase of CML

A
  • 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.
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16
Q

Blast crisis phase of CML

A
  • 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
17
Q

Gleevec

A
  • 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
18
Q

Rationale for use of Gleevac in CML

A
  • 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)
19
Q

Chromosomal Alterations in Cancer

A
  • 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
20
Q

Indications for Bone Marrow Chromosome Analysis

A
  • 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
21
Q

Chromosomal abnormality specifics in CML, ALL

A

t(9;22)(q34;q11.2)

22
Q

Chromosomal abnormality specifics in AML

A

t(8;21)(q22;q22)

23
Q

Chromosomal abnormality specifics in APL

A

t(15;17)(q22;q12)

24
Q

Chromosomal abnormality specifics in AML with EO

A

inv(16)(p13q22)

25
Q

Chromosomal abnormality specifics in MDS/AML

A

5q-,-7,7q-,+8,20q1

26
Q

Chromosomal abnormality specifics in CLL

A

del(13q), +12

27
Q

Chromosomal abnormality specifics in ALL

A

t(1;19)(q23;p13)

t(4;11)(q21;q23)

28
Q

Chromosomal abnormality specifics in Burkitt Lymphoma

A

t(8;14)(q24;q32)

29
Q

Chromosomal abnormality specifics in Follicular Lymphoma

A

t(14;18)(q32;q21)

30
Q

Chromosomal abnormality specifics in Mantle Cell Lymphoma

A

t(11;14)(q13;q32)

31
Q

Solid Tumors - Sarcomas

A
  • In addition to leukemias and lymphomas, some sarcomas also have specific chromosomal abnormalities
  • One example is t(11;22) seen in Ewing sarcoma in which the DNA binding domain of a transcription factor gene, FLI1 is fused with the transactivation domain of EWSR1 gene
32
Q

Karyotypic Patterns in Various Neoplasms

A
  • Acute Leukemias: 60% Simple and disease specific aberrations, 40% multiple and non-specific aberrations
  • Malignant Lymphomas: 48% Simple and disease specific aberrations, 52% multiple and non-specific aberrations
  • Mesenchymal Tumors: 20% Simple and disease specific aberrations, 80% multiple and non-specific aberrations
  • Epithelial Tumors: 3% Simple and disease specific aberrations, 97% multiple and non-specific aberrations
33
Q

Recurrent Chromosome Abnormalities in Epithelial Tumors

A
  • Small cell carcinoma of the lung del(3)(p14-p24)
  • Wilms’ tumor del(11)(p13)
  • Breast HER-2/neu (ERBB2) amplification
34
Q

Non-Small cell Lung Cancer

A

EML4-ALK fusion

35
Q

Ewing’s Sarcoma

A
  • Childhood sarcoma with myogenic and neural differentiation
  • Translocation (11;22)(q24;q12)
  • Results in the fusion of the 3’portion(DNA binding domain) of the FLI-1 gene on chromosome 11 with the 5’ portion (the amino turminus of the EWS gene on chromosome 22)
36
Q

FLI-1/EWS

A
  • FLI-1 is a member of the ETS family of transcription factors with the ets domain that mediates sequence specific DNA binding
  • EWS gene contains RNA binding domain; function unknown
  • FLI-1/EWS fusion product functions as a transcriptional activator
  • Present in 85% of Ewing sarcomas
37
Q

Neuroblastoma

A
  • Third most common childhood malignancy
  • Partial monosomy 1p in 30% of primary tumors
  • MYCN amplification correlates with advanced stage and rapid progression with a poor prognosis
38
Q

Gene amplification

A
  • Amplification of specific genes has been shown to correlate with poor prognosis in several solid tumors including:
  • Neuroblastoma (MYCN at 2p24.3)
  • Breast cancer (HER-2/neu = ERBB2 at 17q12)