Seminar: Genetic Basis of Cancer

GENES
DNA

DNA is made up of two very long polynucleotide chain coiled round a common axis to form a
double helix. Both strands of DNA are reversed in order to form hydrogen bonding properly
between nitrogen bases

Each polynucleotide chain consists of numerous nucleotides

Each nucleotide is made up of 3 parts:

1. Nitrogen bases
2. Phosphate group
3. Pentose sugar
a) Pyrimidine derivatives: Thymine (T) or
Attached to the 5th
Sugar P - backbone
cytosine (C)
carbon atom of the
has a free hydroxyl
b) Purine derivatives: Adenine (A) or guanine sugar of one nucleotide
group linked to 3rd
rd
(G)
& the 3 carbon atom of carbon atom at one

The bases is held together where:

the sugar of adjacent
end & a free
nucleotide by covalent
phosphate group linked
o Two hydrogen bonds hold an adenine
bonds
to 5th carbon atom at
thymine pair together (A = T)
the other end
o Three hydrogen bonds hold a guanine
cytosine pair together (C G)
1.
2.

3.

Functions
Many genes carry instructions for making proteins
Others carry instructions for the sequence of
nucleotides in riposomal RNA (which enter in the
structure of ribosomes) & in transfer RNA (which
carries amino acids during protein synthesis)
Noncoding DNA (DNA that does not code for RNA or
protein); but we still have much to learn about their
function

RNA

Types

Structure:
Adenine, Guanine, Uracil, Cytosine (uracil is present instead of thymine)
Like thymine, uracil base pairs with adenine
Types
Functions
Structures
mRNA
Messenger RNA:

It is copy of DNA genetic code on into mRNA.

transcribed from a DNA

It begins when RNA polymerase binds to a promoter site

template, transfere
on the DNA which direct enzymes to the strand carry
genetic code from DNA
genetic code.
to ribosomes

Next, the two strands of DNA are separated at certain

region (by helicase), and one strand serves as a template
for the formation of a complementary strand of mRNA.

Transcription of part of a DNA molecule with a nucleotide

sequence of ACTGTA results in a mRNA molecule with the
complementary sequence of UGAUAU
rRNA
Ribosomal RNA:
1. Small ribosomal subunit: linked to mRNA at start of
Link with
protein synthesis
mRNA during protein
2. Large ribosomal subunit: contains two important sites
synthesis & enter in
where t-RNA can bind
the components of
Peptidyle site (P): linked to start codon of mRNA; &
the ribosome
contain peptidyl transferase enzyme formation of
peptide bond between amino acids
Aminoacyl site (A): linked to the next 2nd amino acid
codon on the m-RNA
When ribosome moves along m- RNA bringing the
next amino acid into the P & A- sites of ribosome
tRNA
Transfer RNA: carries
1. Amino acid binding site: at which amino acids is attached
amino acids from
2. Anticodon site: its base pairs with the appropriate mRNA
cytoplasm to the
codon at the m-RNA ribosome complex
ribosomes, according to
amino acids code
present on mRNA
GENETIC CODE (CODON)

Represented by a particular sequence of nucleotides in DNA ; transcribed to a complementary

sequence in mRNA; which goes to the ribosome where it is translated into a particular sequence of
amino acids which makes aparticular protein
Properties of genetic code:
1. Each codon reflect an amino acid (20 types)
3. It include start and stop codons
2. Each codon consists of 3 out of the 4 letters (C -G
4. It has 64 different possibilities of base
-U -A) represent the types of nitrogen bases: i.e.
sequences
genetic code is triplets
How the DNA lead the cells to show the genetic trait
This occurs as follows:
1. DNA: carry characteristics of proteins that can be formed by the cell and gives the cell
its genetic characteristics.
2. Cell Enzymes (RNA polymerase): copies the information genes (genetic code of amino acids)
on the DNA molecule in the nucleus (transcription)
3. Messenger RNA (m- RNA) : transfere of genetic code of amino acids to the cytplasm. where it
act as a template for protein synthesis (translation)
4. Transfer RNA (t RNA): carries amino acids from cytoplasm to the ribosomes, and incorporate it
into the polypeptide in its proper place
5. Ribosomal RNA (rRNA) :enter in the components of the ribosome. which is the factory which
manufactures poly peptide chains
6. This protein shows the genetic traits according to its type as follows:
A. Structural proteins: gain cell certain characters as solidification or flexibility
B. Regulatory protein: "enzyme or hormone, or antibody"; stimulates certain interaction to
gain cell a certain ability

Neoplasia (Latin): new growth

Cancer: crab
Cancer is a term used for diseases in which abnormal cells divide without control and are
able to invade other tissues; and spread to other parts of the body through the blood &
lymph systems

Origins of Cancer:

The body is made up of many types of cells. These cells grow and divide in a controlled
way to produce more cells as they are needed to keep the body healthy

When cells become old or damaged, they die and are replaced with new cells

However, sometimes this process goes wrong. The genetic material (DNA) of a cell can
become damaged or changed, producing mutations that affect normal cell growth and
division

When this happens, cells do not die when they should and new cells form when the
body does not need them. The extra cells may form a mass of tissue called a tumor

Monoclonal: Initial neoplastic change affects a single cell

Field origin: Carcinogen acts on large number of cells producing field of potentially neoplastic
cells

NORMAL CELL CYCLE

G2 phase (GAP 2)
More information about if and
when to proceed with cell
division is collected during
this phase. It lasts from 2
to10 hours
S phase (synthesis)
Chromosomes are
copied so new cells will
have the same DNA.
This phase lasts about
18 to 20 hours

M phase (mitosis)
This phase lasts only
30 to 60 minutes,
the cell actually
splits into 2 new
cells (mitosis)

G0 phase (resting
stage)
When the cell gets
the signal to divide,
it moves into the G1

G1 phase (GAP 1)
The cell starts making more
proteins to get ready to
divide and RNA needed to
copy DNA. This phase lasts
about 18 to 30 hours.
Cell division & Regulation

The enzyme RNA polymerase copies genetic codes from DNA to messenger RNA
(transcription)

mRNA is transported to cytoplasm where it act as a template for protein synthesis

(translation)
Ribosomes bind with the mRNA at the codon base (AUG)
The codon base pairs with the complimentary tRNA anticodon
For each base pair an amino acid is added to the polypeptidic chain
At the end of the strand a release factor ends translation and releases the complete
polypeptide from the ribosome which forms Proteins
If the protein produced stimulate cell division it is called mitogenic protein
If it cause malignant transformation oncoprotein
Cell replication is regulated by genetic and environmental factors that promote or arrest
cell division.
Cell multiplicationrequire [RNA-DNA-Enzyme- Protein] all this is under control of
protooncogenes
These genes may be activated by hormones or special mitogenic protein

A. Control of Cell Cycle

How cell division (and thus tissue growth) is controlled is very complex
Cancer is a disease where regulation of the cell cycle and normal cell growth and behavior is
lost
The 5-phase process is controlled by proteins known as cyclin (A, B, D, & E). Which activate
kinases (cyclin dependent kinases : CDK 1, CDK 2, CDK 3, CDK 4, CDK 5, CDK 6)
Cdk (cyclin dependent kinase, adds phosphate to a protein), along with cyclins, are major
control switches for the cell cycle, causing the cell to move from G1 to S or G2 to M
CDKs have a number of control mechanisms
1. MPF (Maturation Promoting Factor): Includes the CdK and cyclins that triggers
progression through the cell cycle
2. P53: a protein that functions to block the cell cycle if the DNA is damaged
If the damage is severe this protein can cause apoptosis (cell death)
P53 levels are in damaged cells. This allows time to repair DNA by blocking the cell
cycle
A p53 mutation is the most frequent mutation leading to cancer
3. P27: a protein that binds to cyclin & cdk blocking entry into S phase
Breast cancer prognosis is determined by p27 levels. Reduced levels of p27 predict a
poor outcome for breast cancer patients
4. P21: It is a potent cyclin-dependent kinase inhibitor (CKI)
It binds to and inhibits the activity of cyclin-CDK2, -CDK1, and -CDK4/6 complexes, and
thus functions as a regulator ofcell cycle progression at G1 and S phase
5. The Rb protein: a tumor suppressor, which negatively control of the cell cycle tumor
progression
It is responsible for a major G1 checkpoint, blocking S-phase entry and cell growth
The retinoblastoma family includes three members, Rb/p105, p107 and Rb2/p130,

collectively referred to as 'pocket proteins'

B. Repair of defects of DNA

= DNA - repair enzymes, working in harmony to recognize and remove a damaged area of DNA,
replacing it with nucleotides complementary to those on the strand opposite the damaged
portion
= All damage in the DNA molecule can be repaired except if damage affects both strands at
the same time

C. Regulation of transcription
DNA has
a) Promotor locus: for initiation of transcription (operator locus)
b) Structural gene: contain the code for protein synthesis
c) Regulatory genes: 3 types:
1. Repressor genes: combined to the operator locus prevent transcription
2. Promotor gene: combined with supressor detach it from the operator locus
transcription
3. Enhancer genes: Combined to DNA at promotor site activation of RNA polymerase
transcription

Mutation

Sudden change in the nature of the hereditary factors controlling certain traits which
leads to change in these traits in the living organism.
The mutation is considered true if it is transferred through different generations.

Types

Origin

1. Gene mutations
Occurs due to changes in the arrangement of the
nitrogen bases of the DNA molecule
These changes lead to the production of a different
enzyme which leads to development of a new trait
Type of gene mutation:
A. Deletion: nucleotide sequence TACGGCATG
TAGGCATG
B. Addition:
C. Substitution: nucleotide sequence CATUAUCCC
CATUAU CGC
2. Chromosomal mutations
A. Change in the number of chromosomes
Loss or gain of one or more chromosomes during
gamete production in the process of meiosis as in
Klinefelter &Turner syndromes in man
Polyploidy: The number of chromosomes may be
duplicated in a cell due to
a) Non separation of the chromatids after centromere
division
b) Failure of membrane formation between the two
daughter cells
B. Change in the structure of the chromosome
Separation of a piece of chromosome during cell
division & its rotation 180 around itself & rejoin the
same chromosome again in an inverted position
II.
Loss or gain of a small segment of a chromosome
III.
Exchange segments between two non-homologous
chromosomes
I.

1. Genetic

Mechanism:
Metabolism,
biotransformatio
n
Inaccurate
repair
mechanisms

2. Dietary

3. Carcinogen
ens

1. Spontaneous
mutations
It originates without
any human
interference
It is due to the effect
of certain
environmental
factors around the
living organisms, as
UV & cosmic rays
It plays an important
role in the evolution
of the living
organisms
2. Induced mutations
Induced by man to
produce desired
changes in the trait
of specific organisms
It is done by using :
X rays ; gamma
rays; UV rays;
Chemicals: such as
mustard gas ,
colchicines, nitrous
acid & others

Predisposing Factors
Mendelian inheritance
B. Polygenic
inheritance

Dominant
Neoplasms occuring
in related individuals

Recessive
more often than
Examples
expected on the basis
a) Retinoblastoma
of chance:
b) Wilms tumor

Breast CA
c) Others

Colon CA
d) Neurofibromatosis (type 1
von Recklinghausens
disease)
e) Multiple endocrine
adenomatosis (MEN)
f) Familial polyposis coli
g) Nevoid basal cell carcinoma
syndrome
a) Caloric intake
b) Protein deficiency, high fat
c) Carotenes & retinoids deficiency
d) Tocopherols deficiency
e) Selenium (glutathione peroxidase) deficiency
f) Zinc deficiency
g) Flavanoids (enzyme inhibition) deficiency
TYPES
A. Physical
I.
Direct effect on DNA
A.

C. Associated with
inherited disease
Many inherited diseases
are associated with higher
risk of neoplasia
Types
a) Syndromes
characterized by
chromosomal fragility
b) Syndromes of
immunodeficiency

Definition:
Substances
known to cause
cancer or
produces an in
incidence of
cancer in animals
or humans
Mode of
carcinogenesis
Inducing
changes in
DNA e.g.
deletion,
breakage,
cross-linkage
Epigenetic
mechanisms:
reversal of
cell
differentiatio
n or
abnormal
differentiatio
n
Synergistic
action with
viruses
Promoter for
other
carcinogens

(radiation)
carcinogens
Types:
UV, X-ray,
Radioisotopes, &
Nuclear Effect

Mode of
oncogenesi
s:

B. Chemical
carcinogens

C. Viral
carcinogens

II.
III.
IV.

Activation of cellular oncogenes

Ionizing radiation: free radicals DNA damage
Solar UV radiation: skin cancers squamous CA, basal
cell CA, malignant melanoma
V.
UV light: induce cross-linkages between DNA molecules &
CA occurs when repair mechanisms are not efficient
VI.
X-ray radiation: Radiotherapy causes radiation-induced
malignancy 10-30 yrs later usually sarcomas. Diagnostic
X-rays are considered to have no risk except in
abdominal x-rays which incidence of leukemia in the
fetus
VII.
Radioisotopes: Radium-containing paints Osteosarcoma.
Thorium risk of liver cancer. Radioactive iodine risk of
cancer 15-25 years later
Action:
a) Direct-acting: act locally without metabolic change
b) Indirect acting: carcinogenic only after being metabolised into
active compounds (procarcinogen ultimate carcinogen)
Types:
1. Air pollution
4. Carcinogenic drugs
2. Dietary pollution
5. Habits
3. Occupational exposure

D. Nutritional carcinogens
1. Hormones
E. Hormonal
inducing
carcinogens

4. Chronic
irritation

5. Developme
ntal
anomalies

Types :
1. Oncogenic RNA Viruses
2. Oncogenic DNA Viruses

a)
b)
c)
a)
b)
c)

Neoplasms:
Estrogen
breast CA
Diethylstilbestro
l (DES) vaginal
& uterine CA

Examples:
1. Papilloma virus
2. Adenovirus
3. Epstein Barr virus

2. Hormonal Dependence of
Neoplasms:

Neoplasm not caused by hormones but

depend on hormones for optimal
growth

Neoplastic cells possess receptors for

binding hormone

Loss of hormonal stimulation slow but

does not halt growth.

Examples: Prostate CA, Breast CA,

Thyroid CA

Irregular teeth
Chronic ulcer
Bilharziasis
Notochord
Dental remnants
Urachus

6. Immune-suppressant
7. Pre-cancerous lesions
a) Neoplastic changes frequently occur in cells
8. Failure of
b) Altered DNA result in production of neoantigens & tumor-associated antigens
immune
surveillanc c) Immune response (cytotoxic) to neoantigens as foreign antigens
d) Neoplastic cells escaping recognition and destruction become clinical cancers
e

THEORIES OF CARCINOGENESIS
1. Viral hypothesis
RNA Retrovirus produces DNA provirus
DNA virus
DNA provirus containing viral oncogene (v Do not contain viral oncogenes
onc) is introduced
Act by blocking suppressor gene
DNA provirus without v-onc is inserted
products
adjacent to cellular oncogene (c-onc) in host Examples HPV, EBV, HBV
cell DNA.
RNA viruses are thought to have acquired vonc.
2. Gene mutation theory: Mutation of structure gene oncoprotein

3. Gene activation theory = EPIGENIC

THEORY
Changes in the regulation of gene
expression [responsible for tissue
differentiation (i.e. epigenetic
mechanism)] rather than in the
genetic apparatus
Cancer cell develop as a result of
reversal of cell differentiation or
abnormal differentiation of a
primitive stem cell
Changes is due to inherited
Stem cells can divide asymmetrically to produce a
abnormalities in the chromosomal or
new stem cell (indicated by a circle) & a progenitor
DNA rather than acquired change in
cell. Progenitor cells divide to produce cells that
DNA
undergo terminal differentiation to produce the
This abnormalities may be
mature cells that make up a tissue or organ
1. Chromosomal aberration
2. Chromosomal or DNA instability
3. Inherited mutation
4. Two - stage mechanism of Carcinogenesis: transformation: initiation, promotion followed
by progression
Carcinogenesis requires 2 hits
1st event initiation: Carcinogen =
initiator
2nd event promotion: Agent = promoter
Initiation
Converts normal cell into dormant tumor cell
Carcinogen Irreversible changes in genetic
material (mutation) cell having the potential
to develop into tumor cell but remain dormant
Promotio Hyperplasia of dormant tumor cell
n
(reversible) to fix the genetic changes
The promoting agents may be : Alcohol,
Tobacco, hormone, etc
Progressi
Dependent tumor cells autonomous
on
malignant cells
5. Multifactors (multistep) theory
1. Promotio Incomplete carcinogen: initiates
Multiple hits occur
n1
Complete carcinogen : both initiates & promotes
5
2. Promotio Induce small foci of pre-neoplastic proliferation
o Each hit produces
n2
where transformed cells live in tissues
a change in the
3. Promoter Endogenous promoters: Hormones (estrogen,
genome which is
s3
prolactin, thyroxin)
transmitted to its
Exogenous promoters
progeny (i .e.
o phenobarbital
clone)
o foreign bodies
o aromatic hydrocarbons (also initiators)
Lag period
o dioxin (most potent in animal studies
o Time between
4. Progressi Proliferation of successful clone
exposure (first
on
Dormancy period in many cases, ends for many
hit) and
reasons (hormonal, nutritional, lymphokines,
development of
immunodeficiency etc.)
clinically apparent
Tumor vascularization, angiogenesis
cancer
Develops into detectable tumor
o Altered cell shows
no abnormality
during lag period

6. Oncogen theory
Oncogenes are genes normally present in the cell and responsible for malignant transformation
once they are changed
Human oncogene includes:
1. Cellular oncogenes:
2. Suppressor oncogenes
(antioncogenes):
Dominant
Recessive
Stimulate cell proliferation
Suppress cell proliferation
Present as inactive Protooncogenes, when Its inactivation or deletion
activated change into cellular oncogenes
cancer cell
Activated by:
Ex: P53
a) Point mutation
b) Translocation
c) Gene amplification
d) Growth factors and Growth receptors
e) Signal-relay or transduction factors

Normal growth regulation is diverted into oncogenesis if:

o Activation of Proto-oncogene
o Inactivation of tumor suppressor gene
Growth factors
Positive growth
Negative
factors
growth factors
Insulin G.F. I &
Transforming
II.
growth factor
Epidermal G.F.
beta.
TNF- .
Platelet
derived G.F.
Gastrin
releasing
factors.
Interleukin 2
Colony
stimulating
factor