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Clinical Genetics
Lecture 4
Cancer
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Between 100-350 out of 100,000 people die of cancer
each year.
One out of every two men and one out of every three
women will develop cancer during their lifetime
(American CancerSociety, 2008).
Caused by abnormal growth and proliferation of cells.
Genetic control system regulate the balance between
cell birth and death in response to growth signals,
growth-inhibiting signals and death signals.
Cell birth and death rates determine adult body size and
rate of growth.
The short life of certain cells is short so cell proliferation
occurs continuously as a constant tissue renewal.
Life of cells
RBCs– 120 days
 WBCs- 13-20days
 Taste receptor cells- 10 days
 Intestinal epithelial cells – few days
 Skin cells- 2-4 weeks
 Muscle cells- 15 years
 Nerve cells-life time
 The cells in adult tissues only proliferate
during healing process.
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Carcinogens
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Lifestyle factors (nutrition, tobacco use, physical activity, etc.)
Naturally occurring exposures (ultraviolet light, radon gas,
infectious agents, etc.)
Medical treatments (chemotherapy, radiation, immune systemsuppressing drugs, etc.)
Workplace exposures
Household exposures
Pollution
Carcinogens do not cause cancer in every case, all the time.
Substances labeled as carcinogens may have different levels of
cancer-causing potential. Some may cause cancer only after
prolonged, high levels of exposure. And for any particular
person, the risk of developing cancer depends on many factors,
including how they are exposed to a carcinogen, the length
and intensity of the exposure, and the person's genetic
makeup.
International Agency for Research on Cancer
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The International Agency for Research on Cancer (IARC) is
part of the World Health Organization (WHO).
Its major goal is to identify causes of cancer. The most widely
used system for classifying carcinogens comes from the
IARC. In the past 30 years, the IARC has evaluated the
cancer-causing potential of more than 900 likely candidates,
placing them into one of the following groups:
Group 1: Carcinogenic to humans
Group 2A: Probably carcinogenic to humans
Group 2B: Possibly carcinogenic to humans
Group 3: Unclassifiable as to carcinogenicity in humans
Group 4: Probably not carcinogenic to humans
http://www.fda.gov/downloads/AdvisoryCommittees/Commit
teesMeetingMaterials/TobaccoProductsScientificAdvisoryCo
mmittee/UCM215717.pdf
Types of mutation
1. Proto-oncogenes: promote normal cell
growth.
 Mutation in PO cause the gene to be
excessively active in growth promotion.
 2.Tumor-supressor genes: restrain
growth
 Mutation in such genes inactivate them and
allow inappropriate cell division.
 3. Caretaker genes: protect the integrity
of the genome.
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Proto-oncogenes (PO)
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PO are a group of genes that cause normal cells to become
cancerous when they are mutated.
Mutations in PO are typically dominant in nature, and the
mutated version of a proto-oncogene is called an oncogene.
PO encode proteins that function to stimulate cell division,
inhibit cell differentiation, and halt cell death. Examples of
proto-oncogenes include RAS, WNT, MYC, ERK, and TRK.
All of these processes are important for normal
human development and for the maintenance of tissues and
organs.
Oncogenes, however, typically exhibit increased production
of these proteins, thus leading to increased cell division,
decreased cell differentiation, and inhibition of cell death;
taken together, these phenotypes define cancer cells.
Thus, oncogenes are currently a major molecular target for
anti-cancer drug design.
How Proto-Oncogenes Become Oncogenes
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More than 40 different human PO are known.
Oncogenes arise as a result of mutations that increase the
expression level or activity of a PO. Underlying genetic
mechanisms associated with oncogene activation include
the following:
Point mutations, deletions, or insertions that lead to a
hyperactive gene product
Point mutations, deletions, or insertions in
the promoter region of a PO that lead to
increased transcription
Gene amplification events leading to extra chromosomal
copies of a PO
Chromosomal translocation events that relocate a PO to a
new chromosomal site that leads to higher expression
Point mutations
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A point mutation, or single base substitution, is a type
of mutation that causes the replacement of a single
base nucleotide with another nucleotide of the genetic
material, DNA or RNA. The term point mutation also
includes insertions or deletions of a single base pair.
Types of point mutation
Transition mutations occur when
a pyrimidine base (i.e.,T or C) substitutes for
another pyrimidine base
 Or when a purine base (i.e.,A or G) substitutes
for another purine base.
 In contrast, transversion mutations occur
when a purine base substitutes for a pyrimidine
base, or vice versa; for example, when a TA or
CG pair replaces the wild type AT pair.
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At the level of translation, when RNA copied from DNA is
converted into a string of amino acids during protein synthesis,
point mutations often manifest as functional changes in the final
protein product.
Thus, there exist functional groupings for point mutations.
These groupings are divided into:
Silent mutations result in a new codon (a
triplet nucleotide sequence in RNA) that codes for the same
amino acid as the wild type codon in that position. In some silent
mutations the codon codes for a different amino acid that
happens to have the same properties as the amino acid
produced by the wild type codon.
Missense mutations involve substitutions that result in
functionally different amino acids; these can lead to alteration or
loss of protein function.
Nonsense mutations, which are a severe type of base
substitution, result in a stop codon in a position where there was
not one before, which causes the premature termination of
protein synthesis and, more than likely, a complete loss of
function in the finished protein.
Chromosomal Translocation
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The exchange of
genetic material
between chromosomes.
Some translocations
cause cancer. And
some translocations
are targets for
emerging, personalized
therapies.
Role of PO
Many PO play an important role during embryogenesis,
because they are often involved in
stimulating cellgrowth and proliferation as
an organism develops.
 Some PO also negatively regulate cell differentiation.
 PO activities are typically turned off once the
developmental processes they regulate are completed.
 However, if PO activity remains high, or if PO are
inappropriately reactivated later in life, cancer may
occur.
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A number of PO code for cell surface receptors.
 For growth and division, cells respond to outside signals
through the binding of extracellular ligands (growth
factors) to the extracellular region of the receptors.
 Upon ligand binding, the receptor undergoes a
confirmational change which in turn leads to activation
of the intracellular domain and a chain of intracellular
events that regulate cell growth, proliferation, or death.
 Examples of PO receptors include EGFR, the receptor of
the epidermal growth factor (EGF) that is involved in
growth factor-mediated signaling, and KDR, the receptor
of the vascular endothelial growth factor (VEGF) that is
involved in angiogenesis.
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Examples of PO
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POcan also code for intracellular proteins that
normally act downstream of cell surface receptor
pathways to stimulate cell growth and division.
Examples of these downstream signaling proteins
include HRAS and KRAS.
Additionally, some PO including cyclin D1
(CCND1) and cyclin E1 (CCNE1), normally act to
push cells through distinct stages of the cell cycle
when the cells receive the appropriate signals.
When these proto-oncogenes are expressed at
higher than normal levels, or when their
expression is inappropriately turned
on, cancer can occur.
Oncogene activation
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Oncogene activation can also arise through
chromosomal translocation events.
The Philadelphia chromosome is the best-known example of an
oncogenic chromosomal translocation.
In this case, one end of chromosome 9 is exchanged with one end
of chromosome 22.
At the broken end of chromosome 22 lies the BCR gene, which fuses with
a fragment of chromosome 9 that carries the ABL1 gene; this
fused chromosome is called the Philadelphia chromosome.
When the chromosome ends fuse, the two genes also fuse with each other
to become BCR-ABL (Heisterkamp et al., 1985).
The fused gene is expressed, and it encodes a protein that exhibits
high protein tyrosine kinase activity, courtesy of the ABL1 half of
the protein. The unregulated expression of this protein activates a
repertoire of other proteins that are involved in cell cycle regulation and
stimulation of cell division.
As a result, the Philadelphia chromosome is associated with chronic
myelogenous leukemia (CML) and several other forms of leukemia.
Targeting Oncogene Addiction to Treat
Cancer
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Short report/review