Part 2 Flashcards
Characteristic of secondary chromosome aberrations
During disease progression as result of clonal evolution
Specific as the cell involved
Can be duplications, monosomies, deletion, trisomy
Related to primary aberrations
T(9,22) (q34, q11) is followed by i(17), +8, +Ph
t(8,21) followed by -Y
Indicated the advanced stage of the disease
Characteristics of primary clinical genetic aberrations
Appear at the beginning of the disease
Characteristic by the cell involved or the mutagenic/carcinogenic agent
Can be translocation, inversion (oncogene), deletion, insertion, monosomy (tumor supressor gene)
Due to there specificity they are diagnostic and prognostic significance
Characteristics and classification of cellular protooncogenes and oncogenes
Protooncogenes are those coding for proteins that help to regulate cell growth and proliferation Act in DOMINANT way!!! Activation by: POINT mutation Chromosome aberration Tumor pomoter integration Demethylation Classifiation of oncogenes: Growth factor: stimulate cell grow Sis-> lead to over production of platelet deliveried growth factor
Growth factor receptor: turn on and off by growth factor
Erb B and erb B2 (GFR gene ampliication)
Her2/neu gene amplification (breast cancer)
Signal transducer: pathways between GF and cell nucleus
abl found in CGL
Ras found in many cancers
Trancription factor: tell the cell to produce protein and RNA
Myc (lung cancer, leukemia, lymphoma)
Programmed cell death regulators: prevent cell from commiting suicide
Bcl-2 (lymphoma cell)
I
Tumor supressor gene
Recessive way (loss of function of both alleles is needed)
Can be caused by deletion, methylation…
Loss of heterozygosity characteristics
Classification:
Control cell division:
RB1 (retinoblastoma) which prevents the progression from G1 to S phase
Repair DNA gene:
HNPCC gene (5% of colon cancer)
Cell suicide gene:
P53 ( Li-Fraumeni syndrome)
Cytogenetic characterization of chronic phase of CGL
Chronic granulocytic leukemia (CGL) or Chronic myelogenic leukemia (CML): over growth of granulocytic precursor cell (myeloblast, promyelocyte, metamyelocyte, myelocyte)
Young, middle age adult (man is more), rare in children
Two phase: chronic phase (bleeding, anemia), acute phase (blastic crisis) overgrowth of myeloblast
Cytogenetics:
t(9,22) (q43,q11)
Molecular change in t(9,22)
Abl (abelson) in chromosome 9 and bcr (break point cluster) in chromosome 22 is translocated result in shorter chromosome 22 which contain bcr/abl fusion gene which code for tyrosine kinase (p210) , it will interact with interleukin 3 receptor result in activation of cell controlling protein, enzyme-> speeding up cell division and inhibit DNA repair
-> causing genetic instability, potentially causing blastic crisis
Cytogenic characterization of accelerated phase of CGL
Criteria:
10-19% myeloblasts in the blood or bone marrow
20% basophils in the blood or bone marrow
Platelets count1000000 unresponsive therapy
New abnormalities add to philadelphia chromosome
Splenomegaly
Characteristic of 2nd aberration:
Their appearance precedes the haematologic transformation
There is correlation between the aberrations and the cellular type of blastic phase
Prognostic value
Comparison of Ph+ CGL and Ph+ acute leukemia
Break point: outside and inside of bcr region
b3a2 and b2a2
Lymphoid vs haematopoietic stem cells
Signiicance of cytogenetic examination in CGL
Comfirm of diagnosis
Subclassification of the disease (chronic, accelerated and blastic crisis)
Prediction of prognosis
Identification of genetic alterations is clinical significance
Classification of acute non-lymphoid leukemia (ANLL)
Acute nonlymphoid leukemia also known as acute myeloid leukemia is the cancer of myeloid line of blood cell which is characteristic by the rapid growth of white blood cell
Most common acute leukemia in adult (1,2% of cancer deaths)
5 years survival (15-70%) relapse rate varies from 78-33%
Chemotherapy and stem cell transplant are the treatment of choice
Classification:
WHO and FAB
WHO classification:
Abnormalies t(8,21) inv(16), t(15,17)
Better prognosis, high relapse rate
Multilineage dysplasia MDS/MPD -> AML is worse prognosis (elderly)
AML and MDS follow chemotherapy, specific chromosome abnormalities, worse prognosis
Not categories AML
Acute leukemias of ambigous( ko ro rang) lineage : can not classify as myeloid or lymphoid cells or have both
French-American-British classification
From M0-> M7
M0 undifferentiated AML
M1 myeloblast no maturation
M2 myeloblast with maturation
M3 promyelocytic or acute promyelocytic leukemia (APL)
M4 myelomonocytic
M4 eo myelomonocytic with eosinophils in bone marrow
M5 monoblast leukemia (5a) monocytic (5b)
M6 erythroleukemia
M7 megakaryoblastic
Cell specific chromosome aberrations in acute non lymphoid leukemia (ANLL)
M1 t(9,22) (q34,q11) t(4,11) (q21,q23) M2 t(8,21) (q22,q22); t(6,9) (p23,q34); t/del (12) (p11-13) M3 t(15,17) (q22,q12) M4 +4 inv/del(16), t(6,9) (q23,q34) M5 t(9,11) (p21,q23); t(11,19) (q23,p13); t(10,11) (p11,q23), t(8,16) (p11,p13) M6 t(1,22) M7 inv(3) (q21,q26)
Agent specific chromosome aberrations in ANLL
Due to expose to chemo therapeutic drugs especially alkylating agents and podophyllotoxins
+8, +21 i(17q), del(20) t(1,3) (p32,q21); t(1,7) (q10, p10)
Poor prognosis
Prognostic significance of primary chromosome aberrations in ANLL
Best t/del (16q); t(15,17) Good diploid t(8,21) Average t(8,21) -Y Bad t(9,22) t/del (11) (q23) ; +8 Worst: -5, -7, complex Monosomy 7 is seperate entity with unfavourable prognosis (bone marrow transplant is indocated)
