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Introduction to Cancer and Mutations
Cancer is the uncontrolled proliferation of cells
...
g
...

Around 150 of these diseases have high survival rates, however there are still a
few with very poor prognosis e
...
pancreatic cancer, the average survival post
diagnosis is 3 months
...

Normal tissue is usually very symmetrical
...

Cells lose contact inhibition and begin to grow over and on top of one another
– known as dysplasia
...
In normal tissue cell
numbers are kept even by a balance between cell division and cell death via
apoptosis
...

A good example of the above situation is the skin
...
Cells in the bottom row
of this layer (basal layer) divide just fast enough to replenish cells as they are
shed from the surface of the skin
...
Therefore, in this situation the number of cells present in
the basal layer remains the same
...
The basal cells now divide faster than is
needed to replenish the cells being shed from the surface of the skin
...
This
gradual increase in the number of dividing cells creates a growing mass of
tissue known as a tumour or neoplasm
...
However, regardless of rate of growth all tumours advance in size
because new cells are being produced faster than they are dying
...


The most severe cases of dysplasia are sometimes called carcinoma in situ (in
place) – this refers to an uncontrolled growth of cells that remain in the
original location
...

Cancers can spread round the body by two mechanisms: invasion and
metastasis
...
Metastasis refers to the ability of cancer cells to
penetrate into lymphatic and blood vessels, circulate throughout the
bloodstream, and then invade normal tissues elsewhere in the body
...
A melanoma (cancer of pigment cells) arising in the skin can have cells
that enter the bloodstream and metastasis to a variety of different organs such
as the liver and brain; note that cancer cells in the liver would be referred to as
metastatic melanoma and not liver cancer
...
The
cancer cells growing in these locations disrupt the function of the organ and
therefore are potentially life threating
...
Malignant tumours are tumours that are capable
of spreading by invasion and metastasis
...


What Causes Cancer?
Cancer is often perceived as a disease that appears for no apparent reason
...

 Intrinsic Factors
o Diet
o Heredity
o Hormones
 Extrinsic Factors

o Some Viruses and Bacteria
 HPV virus has a very strong association with cervical
cancer – vaccination of all 13 year old girls in UK
o Some Chemicals
 Smoking
o Radiation
 UV
 Microwaves – mobile phones?
 Gamma
Cancer ultimately results from the interactions between hereditary and
environmental factors
...
However, practically a
single identifiable factor may be so important that in its absence a significant
number of cancers at a specific site would not occur
...

Studies on people who have move from one country to another suggest that
exposure to risk factors for cancer varies by geographic location
...
This difference has been found to gradually disappear in
Japanese families
...


Carcinogens are molecules that have been found to cause an increase in the
risk of developing cancer
...

 Benzene
Among the various factors that can cause cancer, tobacco smoking is the
greatest public health hazard
...
Cigarette smoking is the main
cause of lung cancer and contributes to many other kinds of cancer too,
including cancer of the: mouth, larynx, oesophagus, stomach, pancreas, kidney
and bladder
...

Some patients of cancer have been found to have a genetic predisposition to
the disease
...

However, cancer is not considered an inherited illness because most patients
of cancer (80-90%) have no family history of the disease
...
These alterations tend to increase an individual’s
susceptibility to developing cancer in the future
...
In general, viruses
are small infectious agents that cannot reproduce on their own, but instead
enter living cells and hijack the cells machinery to produce more copies of the
virus
...
If

this is inserted into a crucial tumour supressing protein, it will inactivate the
protein setting the stage for the cell to become malignant
...
Because a number of mutations
usually must occur for cancer is arise, the longer the person is alive the more
time these mutations have to develop and accumulate
...
Because
people today are living longer than they did 50 or 100 years ago, these
mutations have more time to accumulate
...


20-Year Lag Time Between
Smoking and Lung Cancer
Cigarette
consumption
(men)
4000
3000
Cigarettes
Smoked
per Person
per Year

150

Lung
cancer 100
(men)

2000
1000

50

1900 1920 1940 1960 1980
Year

Lung Cancer Death
(per 100,000 people

Carcinogens act through a multistep process that initiates a series of genetic
alterations and stimulate cells to proliferate
...
There can be a delay of several decades
between exposure to the carcinogen and the onset of cancer
...
g
...
This period
between exposure and onset is called the ‘lag time
...
The simplest type of mutation
involves a change in a single base along the base sequence of a particular gene
– very similar to a typo in a word that has been misspelled
...
Sometimes, large segments of a DNA
molecule are accidentally repeated, deleted or moved
...
Mutations have been found in genes that activate and deactivate
carcinogens and in those that govern the cell cycle, apoptotic genes, cell
signalling and cell differentiation
...

Cancer may begin because of the accumulation of mutations involving
oncogenes, tumour suppressor genes, and DNA repair genes
...
The proliferating cells then tend to acquire
additional mutations involving DNA repair genes, other tumour suppressor
genes, and many other growth-related genes
...
In other words,
creating a cancer cell requires that the brakes on cell growth (tumour
suppressor genes) be released at the same time that the accelerators for cell
growth (oncogenes) are being activated
...
On mutation in a pre-cancerous cell makes it more likely that other
mutations will persist in the genome – deletion of DNA repair genes is a good

example
...
These mutations confer a
growth advantage to cancer cells when compared to wild type cells
...
However, as each new cell is
formed, the genome in the new cell may acquire different mutations than to
its neighbour
...
Some cells may have gained resistance to chemical attack
by chemotherapy and will survive while other cancer cells die
...

Gene Mutations
Bases are read in threes and each set of three is referred to as a codon
...
Base Substitution
a
...
Base Insertion
a
...
Base Deletion
a
...
Missense Mutation
a
...
There is a change in the amino acid sequence of the resultant
protein

c
...
If the chemical properties of the amino acids are similar, the
mutation is said to be conservative
e
...
Nonsense Mutation
a
...
There is a premature termination in translation
c
...
Silent Mutation
a
...
There is no change in the amino acid sequence of the resultant
protein
c
...
Mutations within the promotor can lead to increased or
decreased levels or inappropriate translation
...
Mutations at the intron-exon borders can affect correct splicing of the
mRNA
...
This is a signal for the enzymatic removal of the intron
...
i
...
intron sequences can be included in spliced mRNA or part of
exons can be spliced out
...


DNA Damage and Repair
The genome of each cell undergoes approximately 20,000 DNA damaging
events and approximately 10,000 replication errors per day
...
This is critically important as it ensures that the DNA we inherit is the
DNA we pass onto future generations
...

There are many different types of DNA Damage…
1
...
Small chemical changes to the structure of
the DNA bases
i
...
Spontaneous depurination - Called
an AP site – a location in DNA with
neither a purine or a pyrimidine
iii
...
Oxidation
3
...
Single strand and double strand
breaks
4
...
Helix distorting changes to
the DNA bases - UV-induced
thymine dimers
…
...
Most
damage to DNA is repaired by the removal of the
damaged bases followed by resynthesis of the
excised region
...
Only a few types of DNA damage are repaired in
this way, particularly pyrimidine dimers resulting from exposure to UV light
and alkylated guanines
...
The bond between uracil and the deoxyribose is cleaved by
a DNA glycosylase, leaving a sugar with no base attached in the DNA (an AP
site)
...

The remaining deoxyribose is removed by deoxyribosephosphodiesterase
...

However, there are plenty more mechanisms:
 Direct reversal
o Photolyase – UV damage
 Prokaryotes only
o MGMT
 O-6-methylguanine-DNAmethyltranserfase
o Oxidative dealkylation
 Excision Repair
 Repair of double – strand breaks
o Homologous recombination (error free)
o Non-homologous end-joining (error prone)



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