Cancer and its types

1. CHRONIC MYELOID
LEUKEMIA
JENITA J
M.SC BIOCHEMISTRY

2. CANCER
• Cancer is a genetic disease characterized by unregulated growth and dissemination of
malignantly transformed neoplastic cells.
• The process of cancer development goes through several stages of biochemical and
genetic alteration in a target cell.
• Cell cycle and check point genes are found mis regulated or mutated in cancer.
E.g.: protooncogenes, tumours suppressor genes etc.
• Changes or mutations in the cell genome cause DNA mutations produce proteins
(oncoprotein).
• That disrupt the delicate cellular balance between division and quiescence, resulting in
cells that keep dividing to form cancers.

3. Benign tumour
Benign tumours is a mass of cells that lacks the ability
to either invade neighboring tissue or metastasize.
They cannot spread by invasion or metastasis hence
only grow locally.
Malignant tumour
Malignant tumours are capable of spreading by
invasion and metastasis.
Types of cancer
Carcinoma, Sarcoma, Leukemia,
Lymphoma, Myeloma ,Germ cell tumour,
Blastoma.

4. LEUKEMIA
• Leukemia is a clonal proliferation of hematopoietic stem cells in the bone marrow.
• A progressive, malignant disease of the blood forming organs, characterized by distorted
proliferation and development of leukocytes and their precursors in the blood and bone
marrow.
• Leukemia comes from the Greek leukos which means ‘white’ and aima which means ‘blood’.
• About 3-4 per 100000 population in india.
• 30% to 50% of all childhood cancers in male and 19%-52% in females.
• The exact cause is unknown. Several factors associated with leukemia are
 Genetic factors :hereditary abnormalities (down syndrome)
identical twins ,fraternal twins etc
 Over exposure of ionizing radiations( radio active substance) and
chemicals(benzene).
 Congenital abnormalities
 Primary immunodeficiency
 Infection with human T-cell Leukemia Virus.
 Environmental factors.

5. CLASSIFICATION OF LEUKEMIA
• MYELOID LEUKEMIA
• LYMPHOID LEUKEMIA
• CHRONIC LEUKEMIA(slow growing)
• ACUTE LEUKEMIA (fast growing)

6. ACUTE MYELOID
LEUKEMIA
ACUTE LYPHOBLASTIC
LEUKEMIA
CHRONIC MYELOID
LEUKEMIA
CHRONIC LYPHOBLASTIC
LEUKEMIA
 Characterized by the
development of immature
myeloblasts in the bone
marrow.
 It occurs at any age but
occurs most often at
adolescence and after age of
55.
 It arising a single lymphoid
stem cell, with impaired
maturation and accumulation
of the malignant cells in the
bone marrow(B cells).
 Common type in children 2-9
yrs,15% in adults, before 14
yrs.
 Chromosomal abnormality
 Philadelphia chromosome.
 Occurs between 25-60 of age.
Peak 45 year.
 It is characterized by proliferation of
small, abnormal, mature B
lymphocytes, often leading to
decreased synthesis of immunoglobulin
and depressed antibody response.
 Increases with age and is rare under
the age of 35. It is common in men.
The main types of leukemias

7. CHRONICMYELOIDLEUKEMIA
• Chronic myeloid leukemia (CML) is a myeloid stem cell neoplasm characterized by
uncontrolled accumulation and expansion of myelopoietic stem and progenitor cells.
• The reciprocal chromosomal translocation t (9;22) that creates the fusion oncogene
BCRABL1.
• Epidemology
• 15% of all cases are CML. CML is the commonest adult leukaemia in India and the annual
incidence ranges from 0.8– 2.2/100,000 population in males and 0.6– 1.6/100,000 population in
females in India.
• Male predominance.
• The median age of diagnosis is 38-40 years.
• In this year US about 8,450 new cases will be diagnosed with CML (4,970 in men and 3,480 in
women).About 1,130 people will die of CML (670 men and 460 women).

8. Chronic
phase
•CML begins with excessive proliferation of myeloid cells of intermediate grade
(i.e. myelocytes and metamyelocytes) and mature segmented neutrophils.
•An Initial indolent period that may last 3 to 4 years.
• Symptoms -a loss of wellbeing, fatigue, purpura, anaemia, weight loss and
abdominal discomfort.
• Disease is relatively stable and responds to conventional therapy.
Accelerated
phase
•An accelerated phase of CML is also described in which there is progressively
rising leucocytes is associated with thrombocytosis or thrombocytopenia,
worsening anemia, clonal evolution and splenomegaly.
• Median duration upto 1 year.
•Increase blood basophils, increasing marrow or blood blasts (up to 19%).
•Symptoms include fever, poor appetite, weight loss,
•Less responsive to standard treatment, presence of Ph chromosome
Blastic
phase
•Blastic phase or blast crisis in CML fulfills the definition of acute leukemia in
having blood or marrow blasts >20%. Median survival 3-6 months.
•Accumulation of blasts in extramedullary sites(e.g Bone, CNS, Lymph nodes, Skin.
•Symptoms include fever, poor appetite, weight loss
•Poor response to traditional treatment.

9. PHILADELPHIA CHROMOSOME
• In 1960 Nowell and Hungerford described a minute
chromosome 22 in CML cells that became known as
Philadelphia Ph chromosome.
• In 1973 Rowley revealed the reciprocal translocation between
9 and 22 t(9;22) (q34;q11).
• ABL1 (Abelson ) on 9q34 and BCR (break point cluster
region) on chromosome 22q11.
• As a result of the (9;22) translocation, the BCR ABL1 fusion
gene is formed on the derivative of chromosome 22 (22q-
,Ph),whereas the reciprocal ABL1-BCR residues on the
derivative of 9q+ resulting in a BCR-ABL transcript.
• The location of the genomic breakpoints of BCR and ABL1
are BCR exon 13 and ABL1 exon 2 or exon 14 and exon 2.
Nowell and Hungerford Rowley

11. MECHANISM OF IMATINIB MESYLATE
Imatinib is FDA approved for use as a
first-line treatment for people with
accelerated phase or blast crisis CML or
chronic phase CML patients in 2001.
Imatinib mesylate, a potent inhibitor of
Abl tyrosine kinase and highest
selectivity for growth inhibition of Bcr–
Abl expressing cells.
Orally administered inhibitor of BCR-ABL
tyrosine kinase thus it targets the
molecular pathogenetic event in CML.
BCR-ABL
(Tyrosine
kinase)
Signaling
pathways
• Ras
• AKT
• PI3K
• Other
pathways
Deregulation
• Cell
proliferation
• Cell survival
• DNA repair
CML
• WBC 
• RBC 
• Platelets 
+
Tyrosine kinase inhibitors
(TKIs)
-
> >

12. CONVENTIONALCYTOGENETICANALYSIS
• Cytogenetics is the study of genetic
phenomena through the cytological
analysis of chromosomes under the
electron microscope. Cytogenetic
analysis of karyotypes has been, the
standard method to detect the Ph
chromosome t(9;22)and the
Additional Chromosomal
Abnormality (ACA).

13. Group A Chromosome1and3
Chromosome 2
Large metacentric
Large sub metacentric
Group B Chromosome 4-5 Large sub metacentric
Group C Chromosome 6-12 and
X
Medium sized Sub
metacentric
Group D Chromosome 13-15 Large Acrocentric
Group E Chromosome 16-18 Relatively short
metacentric or sub
metacentric
Group F Chromosome 19-20 Short metacentric
Group G Chromosome 21-22
and Y
Small Acrocentric
KARYOTYPING
The systematic arrangement of chromosome from a cell according to their length, position of centromere and
specific banding pattern is known as karyotyping.

14. KARYOTYPE OF MALE AND FEMALE CML PATIENTS SHOWING
THE PRESENCE OF PHILADELPHIA CHROMOSOME
Karyotype of male CML patient showing 46,XY,t(9;22)(q34;q11)

15. CONVENTIONALCYTOGENETICSAND FLOURESENCEINSITUHYBRIDIZATION
(FISH)
• Cytogenetics is the study of structure
function and evolution of
chromosomes.
• Also, FISH technique is useful in
cases where no metaphases can be
obtained, as it allows examination of
interphase nuclei.
Abl – Ch 9
Bcr- Ch 22
Bcr-Abl Fusion
Red → Bcr probe
Green → Abl Probe
Yellow → fusion of Bcr and Abl
Ch 9 Ch 22

16. FISH PROCEDURE
Prepare slides with metaphase chromosomes
or interphase nuclei.
Dehydrate in ethanol
Denature DNA at 70 C
Denatured labelled probe.
Incubate at 37 C for 4-16 hours for
hybridization.

17. (A) FISH image showing interphase nucleus of a CML patient with one orange signal (ABL gene), one
green signal (BCR gene), and one orange-yellow-green fusion signal (BCR-ABL fusion gene) [OGF].
(B) Metaphase spread observed in a CML patient with one orange (ABL gene on chromosome 9), one
green signal (BCR-ABL fusion gene on chromosome 22) [OGF pattern].
46,XY,t(9;22)(q34;q11)

18. CONCLUSION
• Cytogenetics is a crucial tool for diagnosis, prognosis and treatment of CML. Bone
marrow Karyotyping is useful for specific identification of the cytogenetic profile.
• The molecular technique like Fluorescent in Situ Hybridization (FISH) also has an
important role in the detection of recurrent chromosomal abnormalities in CML.
• The patient sample lacks cell division or low quality metaphases were not able to
analyze in conventional cytogenetics while the presence of BCR-ABL fusion gene could
be detected using molecular technique FISH.
• Time is much shorter in the case of FISH than conventional cytogenetics.
• The presence of Ph chromosomes and other ACA were confirmed by interphase and
metaphase FISH analysis.
• It helps in the early diagnosis and thereby increased the survival outcomes by the
quality treatment.