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Genetic Basis Of Cancer

Clinical Biochemistry
At the end of the lecture…….
 Cell cycle and its control.
 Proto-oncogene, oncogene, tumor-suppressor
genes.
 Mechanism of carcinogenesis.
 Carcinogenesis and environmental factors.
 Cytogenetic changes in cancer.
 Sporadic and familiar cancers: cytogenetic factors of:
 o Cancer breast.
 o Cancer colon.
 o Leukemia.
Q: A 35-year-old Jewish woman of Ashkenazi descent is evaluated in the
office during a routine examination. Her medical history is noncontributory.
The family history includes a paternal grandmother who had bilateral breast
cancer at ages 42 and 50 years and died of metastatic breast cancer at age
53 years and a paternal great aunt who had ovarian cancer at age 45 years
and breast cancer at age 51 years. Her two sisters, mother, and mother's
relatives have not had breast or ovarian cancer, and her father is healthy
without any cancer.

Physical examination, including breast and pelvic examination, is normal.

Which of the following is the most appropriate next step in management?


A Genetic counseling
B Low-fat diet
C Prophylactic bilateral mastectomy
D Prophylactic oophorectomy
E Tamoxifen
Cancer:
• Cancer is one of the most common diseases
in the developed world.
• Lung cancer is the most common cancer in
men
• Breast cancer is the most common cancer in
women
• There are over 100 different forms of cancer
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• The division of normal cells is precisely
controlled.
• New cells are only formed for growth or to
replace dead ones.
• Cancerous cells divide repeatedly out of
control.
• Cancerous cells can also destroy the correct
functioning cells of the major organs.

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Heterogeneity of cancer progression.

Welch H G , Black W C JNCI J Natl Cancer Inst


2010;102:605-613

Published by Oxford University Press 2010.


Model of Genetic Susceptibility
to Neuroblastoma

Maris, JM June 2010 NEJM


Cancer
 Uncontrolled cellular
proliferation
 Cancer is a genetic disease
 About 5-10% caused by
inherited genetic mutations
 Majority by cumulative
effect of somatic mutations
 Cancer is a disease of cell
cycle

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The “cell cycle”

Def. is the series of events that take


place in a cell leading to its
division and duplication.

Steps of the cell cycle:

• Presynthetic phase, Gap 1 (G1)

• DNA synthesis phase, S phase (S)

• Postsynthetic phase, Gap 2 (G2 )

• Mitotic phase, (M)

• Gap 0, (G0 ): A resting phase


Cell cycle: Proliferating cells
G1: Newly born cell
Short period proliferating cells

S: Replication of DNA
G2:
Cell death M: Mitosis

G0: Non-proliferating cell


Quiescence

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DNA helicases: Unwinding
DNA binding proteins: Prevents winding back
DNA primase: formation of DNA/RNA primer (from free
nucleosides in cell)
DNA polymerase: Catalyse elongation of new strand (5’ - 3’)

Lagging strand:
DNA ligase: Connects Okasaki fragments
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Control of the Cell Cycle

 The passage of a cell


through the cell cycle is
controlled by groups of
proteins :
1- Cyclins
2- Cyclin-dependent kinases
(Cdks)
 Transition through each
phase of cell cycle is
mediated by specific
cyclin/Cdk
3- Cyclin-dependent kinases
inhibitors (CdkI)
Control of the Cell Cycle

4- Checkpoints:
 G1/S checkpoint.
 G2/M checkpoint.
 Spindle checkpoint.
All checkpoint examined
require the service of
complex proteins as:
o Retinoblastoma protein
o P53 protein

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Role of Rb protein in Cell Cycle Control

Rb Protein is Inactivated By CDK-Cyclin During G1  S


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Role of p53 protein in Cell
Cycle Control

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Characters of Caner Cells
• Uncontrolled growth
• Invasion
• Metastasize -- that is, establish new
tumour sites at other locations
throughout the body.
“Secondary tumours”.
Mechanism Of Carcinogenesis
What Are The Genes Involved In
Cancer Development?

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Types Of Genes Which May Cause Cancer

1) Proto-oncogenes and oncogenes


2) Tumour suppressor genes
3) DNA repair genes
4) Genes that regulate apoptosis

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NORMAL CELL

Growth factor
Growth factor receptor

cytoplasm

Signal transduction

Activation of
transcription
nucleus

1. Proto-oncogenes are normal cellular genes whose products promote cell proliferation
 Proto-oncogenes include a heterogenous family of genes with many
biochemical effects:

1. Growth factors as FGF


2. Growth factor receptors
as erb-2, ret

3. Signal transducing
factors
as cytoplasmic kinases

4. DNA binding
5. cell cycle proteins concerned
proteins as cyclin with transcription
D
Oncogenes
• Are genes capable of causing cancer
• Were first recognized as unique genes of tumor
causing viruses.
Proto-oncogenes:
• Are DNA sequences in normal cells that looks
like or identical to oncogenes but don’t cause
cancer.
• Their products may play roles in cell
differentiation.

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NEOPLASTIC CELLS
Oncogenes can promote uncontrolled cell proliferation by
several mechanisms

Increase Increase in
Increase Increase in
In growth factor activation of
In growth signal
receptors transcription
factor transduction

EGF amplification in Ras point mutation in MYC translocation in


FGF amplification in Burkitt lymphoma
breast, ovarian& lung lung, colon &
breast &bladder
cancer pancreatic cancer
cancer
(1) Proto-oncogenes
Proto-oncogenes may be activated & converted to
oncogenes by:

1 2 3
Point Chromosomal Amplification
mutation translocations
Activation Of Proto-Oncogenes To Oncogenes
Activation means: increased transcription of their genes.
Five mechanisms activate proto-oncogenes:
• 1. promoter insertion
Certain retroviruses integrate their genome as cDNA in host
cells, this cDNA is flanked by sequences termed long terminal
repeats that function as promoters for transcription of proto-
oncogenes
• 2. enhancer insertion:
The integrated viral genome in host cell may be inserted
down stream or upstream from the proto-oncogene but in
the reverse direction (enhancer sequence present in long
terminal repeats)
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3. chromosomal translocations:
• It is one type of chromosomal
change seen in tumor cells:
• Piece of one chromosome is split
off and joined to an other
chromosome, if the second
chromosome donates material to
the first, then it is reciprocal
translocation.
• An example of translocation is the
philadelphia chromosome involved
in chronic granulocytic leukemia
(chromosome 9 and 22)
• 4. Gene amplification:
 One method of bringing about gene
amplification is by administration of the
anticancer drug methotrexate.
 Is an inhibitor of dihydrofolate reductase.
 tumor cells can become resistant to it by
amplification of its gene and as
consequence there is increased rate of
enzyme activity.

• 5. Point mutation:
Transition
transversion

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Mechanism of action of oncogenes:
• 1. May act on key intracellular pathways
involved in growth control, uncoupling them
from the need to exogenous stimulus.
• 2. their products may imitate certain growth
factors
• Humans of all ages can develop cancer and
various tissues are affected

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Types Of Genes Which May Cause Cancer

1) Proto-oncogenes and oncogenes


2) Tumour suppressor genes
3) DNA repair genes
4) Genes that regulate apoptosis

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(2)Tumour suppressor genes

 Both alleles need to be


mutated or removed in
order to lose the gene
activity.
 The best examples are:
(I) Retinoblastoma
(Rb) Gene
(II) p53 Gene

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Types Of Genes Which May Cause Cancer

1) Proto-oncogenes and oncogenes


2) Tumour suppressor genes
3) DNA repair genes
4) Genes that regulate apoptosis

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(3) DNA Repair Genes

 Correcting errors in DNA


 Defective protein permit mutations to occur in other genes
during normal cell division 33
Types of cancer genes

Type of gene Normal function Mutated function Types of proteins


Oncogene Promotes division Promotes division Growth factors
- abnormal time or
cell type

Tumor Suppresses cell Fails to suppress Checkpoint


suppressor division division molecules
gene

DNA repair Repair DNA Fail to repair DNA Enzymes for


gene mutation mutations mutations mismatch or
excision repair

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Types Of Genes Which May Cause Cancer

1) Proto-oncogenes and oncogenes


2) Tumour suppressor genes
3) DNA repair genes
4) Genes that regulate apoptosis

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(4) Genes that regulate apoptosis

 Genes that promote


apoptosis e.g., BAX, BAK
 Genes that inhibit apoptosis
e.g. BCL2, BCL-XL.

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Cancer Is A Multistep Process Resulting From A
Series Of Mutations In A Single Cell

 Carcinigenesis is a multistep process. Accumulation of damage


to multiple genes → Cancer
Tumors develop from single transformed cell. Over time, tumors can acquire
excessive growth, new mutations, and escape from the immune system a process
called tumor progression.
Cytogenetic or Karyotypic changes in cancer

point mutations
Translocations
Deletions
Amplification
Aneuploidy.
The Seven fundamental changes in cancer

 The carcinogenic
process include
seven fundamental
changes in cell Genomic
instability
physiology that
resulting
together lead to from
cancer defects in
development DNA repair

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Hereditary in cancer

Hereditary forms of cancer can be divided


into three categories:
1. Inherited cancer syndromes
2. Familial cancers
3. Autosomal recessive syndrome of
defective DNA repair

Hereditary predisposition – Some families are more


susceptible to getting certain cancers.
Remember you can’t inherit cancer, it is just that you
maybe more susceptible to getting it.

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Hereditary breast cancer

 Mutation in two genes,


BRCA1 and BRCA2,
account for 80% of cases
of familial breast cancer.

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Hereditary non polyposis colon carcinoma
syndrome

 Characterized by familial carcinoma


of the colon affecting mainly the
cecum and proximal colon resulting
from defect in genes involved in
DNA mismatch repair.

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Leukemia
 Chronic myelogenous leukemia (CML)
 In 90% of cases, reciprocal and balanced chromosomal translocation
between chromosomes 9 and 22 that generates the Philadelphia
chromosome.
N.B.:
• Cancer arises from the mutation of a normal gene.
• Mutated genes that cause cancer are called oncogenes.
• It is thought that several mutations need to occur to give rise
to cancer
• A factor which brings about a mutation is called a mutagen.
• A mutagen is mutagenic.
• Any agent that causes cancer is called a carcinogen and is
described as carcinogenic.
Carcinogenic agents

 Definition:
Carcinogenic agents are
substances that cause
genetic damage and
produce neoplastic
transformation.
Carcinogenic agents

 Types of carcinogens
1. Physical carcinogens
2. Chemical carcinogens
3. Oncogenic viruses
Physical Carcinogens
Types:

(1) (2)
Ultraviolet rays: Ionizing radiations:
Cause skin carcinoma and Cause leukemia
melanoma
(3) X-rays
Physical Carcinogens

(3) UV rays and X-rays cause DNA damage:


• Pyrimidine dimers
• A purinic or a pyrimidinic sites
• Single or double strand breaks
• Cross linkage
• Or damage through formation of free radicals
in tissues.

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Carcinogenic chemicals and drugs:
• Polycyclic aromatic hydrocarbons
• Aromatic amines
• Nitrosamines
• Drugs: cyclophosphamide
• Alkylating agents
• Inorganic compounds: arsenic, lead, asbestos…
• Naturally occurring compounds: Aflatoxin which is
produced by aspergillums flavus and contaminate
peanuts.

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Chemical carcinogens
 Indirect-Acting Agents  Direct-Acting
Agents

Aromatic Azo dyes Aflatoxins B1 Alkylating agents


polycyclic → cancer → liver cancer used for
hydrocarbons in bladder chemotherapy →
tobacco smoke → cancer
lung cancer
Chemical Carcinogens: Aflatoxin (cont.)

• Aflatoxin B1 causes liver


cancer.
Chemical Carcinogens (cont.)

Nitrosamines and Asbestos → lung Vinyl chloride Nickel → lung


amides cancer & → liver, brain, cancer
→ gastric cancer mesothelioma lung cancer
 Tobacco smoke
 Pollution

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Oncogenic Viruses
 Types: Oncogenic viruses are either
1. DNA viruses

 Hepalitis B virus →  EBV → Burkitt’s  Human Papillomavirus


hepatocellular Lymphoma (HPV, 16,18) → squamous cell
carcinoma carcinoma of the cervix.
Oncogenic Viruses (cont.)
2. RNA viruses
Human T-cell leukaemia virus-
1 → T cell lymphoma and
leukemia).
Metabolism of chemical carcinogens
By Cytochrome P450 in ER; that is affected by
many factors as:
• AGE
• SEX
• GENETIC VARIATIONS
• SPECIES

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Biochemical Changes In Cancer Cells
• Increased rate of glycolysis
• Change of cell surface glycoprotein, glycolipids
• Alteration of cytoskeleton structures like actin filaments
• Increased secretion of growth factors in the surrounding
medium
• Increased activity of ribonucleotide reductase
• Increased synthesis of DNA and RNA.
• Increased aerobic and anaerobic glycolysis
• Synthesis of fetal proteins e.g carcinoembryonic antigen
• Decreased catabolism of pyrimidines
• Inappropriate synthesis of certain growth factors

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