Topic 11-13: Genetic & Molecular Basis for Variation in Cancer
Organisation of Eukaryotic Genome
Genome: The entire set of genetic material for all the proteins and RNA that the organism will
ever synthesise to direct the development and maintenance of that organism.
*DNA present in a haploid set*
1. Genes are carried on chromosomes, the vehicles of inheritance. Each gene resides in a
gene locus.
2. The majority of eukaryotic genes are distributed among a species-specific number of linear
chromosomes.
3. Every eukaryotic cell has a complete copy of the nuclear genome. A eukaryotic cell with a
hybrid genome or a complete genome comprises of a haploid set of linear chromosomes,
mitochondrial genome and chloroplast genome
4. The human genome is distributed over 22 pairs of different autosomes and one of the two
sex chromosomes X/Y.
5. In general, more complex organisms tend to have larger genome sizes; there is a
correlation between an organism’s genome size and its apparent biological complexity
because more genes and gene products are required to direct the development and
maintenance of more complex organisms.
6. Generally, gene size is also larger in more complex organisms due to the increase in the
proportion of regulatory sequences needed for more complex control of gene expression.
7. However, there is no correlation between biological complexity and number of genes in
organisms
8. Genome size is not necessarily proportional to number of genes in the genome
9. Prokaryotic genomes have much higher gene densities than that of eukaryotes
10. More complex eukaryotes generally have lower gene density than lower eukaryotes;
decreased gene density is principally attributed to the large proportion of non-coding
intergenic DNA relative to genes present in their genomes
11. A eukaryotic gene includes not only the coding sequence, but also regulatory nucleotide
sequences required for proper expression of the gene
12. The total number of genes represented in the human genome is ~1.5%; the remaining is
allocated to non-coding DNA
13. Genome = (non-coding DNA regulatory sequences) + (Exons + introns = transcription unit)
14. Exon:
I. Interrupted by introns
II.
Described as discontinuous coding DNA sequences
15. Intron:
I. Not represented in amino acid sequence
II.
Number and size per gene varies
III.
Generally longer than exons
Types of eukaryotic genes
Solitary genes
Features
 Genes that are present in only one copy per haploid set of
chromosomes (eg. Chicken lysozyme gene)
Topic 11-13: Genetic & Molecular Basis for Variation in Cancer
Mutigene
families
Tandem
Dispersed
 Multiple copies of an (almost) identical gene sequence are
clustered together in tandem to form a tandem repeated array
 Encode for identical or nearly identical proteins or functional RNAs
 Gene products are usually required in heavy demand within the cell
 Allows for some RNAs and proteins to be produced in large
quantities
 Consists of genes with very similar by non-identical DNA sequences
 Members can be located within 5-50kb of one another, forming a
cluster on the same chromosome, or they may be dispersed on
different chromosomes
 Encode for proteins with close but non-identical amino acid
sequences, and which usually have related or even identical
functions
 These proteins are closely-related and typically constitute a protein
family (eg. α/β-globin of haemoglobin)
 Members of a gene family encode gene products that may be
expressed at different times in development or in different
tissues/cell types
Repetitive DNA
Features
 Sequences present in multiple copies in a genome
 Tandemly repeated DNA/tandem arrays consist of DNA sequences repeated multiple times and
arranged adjacent to one another in a head-to-tail fashion
Tandemly repeated Regular
 14-500 bp
genes: Satellite DNA satellite DNA  Very large clusters of hundreds to thousands of kb
– mostly consists of
 More common, major constituent of centromeric DNA
relatively short
Minisatellite  10-100 bp
sequences repeated
 Sizeable clusters of 0.1 to hundreds of kb
many times in
 More frequently located towards ends of chromosomes,
tandem to form long
including telomeric DNA
array/ cluster in a
Microsatellite  Small clusters of <150 bp
localised area of the
 Evenly distributed along the length of chromosomes
genome
Regulatory sequences: Regions of DNA sequence where gene regulatory proteins bind to control
the rate of assembly of protein complexes required for gene expression
Non-coding DNA
Gene
Intron
Promoter
Intergenic
Promoterproximal
centromere
untranslated
regions
Telomere
Distal control
elements
Topic 11-13: Genetic & Molecular Basis for Variation in Cancer
Structure
Function
Intron
DNA sequences
interrupting exons,
exons are thus
discontinuous DNA
sequences
Regulatory
sequences may exist
Allows for
alternative splicing,
so that different
combination of
exons may give rise
to different protein
products
5’ Untranslated regions
5’ UTR starts at the +1 position
on DNA template strand where
transcription begins and ends
one nucleotide before the
triplet base which codes for
the start codon of the coding
region
Contains DNA sequence which
is transcribed into a ribosome
binding site on mRNA for
proteins which regulate the
mRNA’s stability or translation
3’ Untranslated regions
3’ UTR starts after the
triplet base on DNA
template strand which
codes for a stop codon
Contains the triplet base
on which codes for a stop
codon
Contains DNA sequences
which is transcribed into a
polyadenylation signal on
mRNA, which is needed for
termination of
transcription
Replicative cell senescence: the period in which a cell withdraws permanently from the cell cycle
and hence stops dividing after reaching Hayflick limit when it has divided for 25 to 50 cell divisions
End Replication Problem:
1. The end-replication problem occurs in linear chromosomes as the standard DNA replication
machinery is incapable of completely replication all the way to the ends of a linear chromosome,
leading to shortening of telomeres with each successive cell division
2. Each time a cell with linear chromosomes divide, a small section at the extreme 3’ end of the
parental strand does not undergo DNA replication due to the lack of an upstream DNA
polymerase that can fill in the gap generated by the removal of the final Okazaki primer.
3. Hence, the telomeres shrink by approximately 100 base pairs with every successive cell division.
This represents about 16 tandem repeats of TTAGGG.
4. Without telomeres, vital genetic information that is needed to sustain a cell’s activities will be
lost.
Centromere
Structure  Consists of satellite DNA (alpha satellite
DNA in humans) that consists of short,
AT-rich sequences that are repeated
thousands of times in tandem
 Centromeres are embedded in a very
large stretch of centric
heterochromatin: centromeric DNA in
centric heterochromatin is bound by
Telomere
 Consists of specialised nucleoprotein
which are complexes composed of
telomeric DNA bound by specific
proteins
 Telomeric DNA consists of long
stretches of hundreds to thousands of
tandem repeats of a short nucleotide
sequence with high G content
Topic 11-13: Genetic & Molecular Basis for Variation in Cancer
Function
specialised nucleosomes containing a
centromere-specific histone and other
centromere-specific proteins that
compact the nucleosomes into dense
arrangements
 Folding of DNA into these specialised
nucleosomes facilitates the assembly of
other centromere-binding proteins to
form the kinetochore that associates
the centromere to the mitotic spindle
1. Sister chromatid adhesion: centromere
is the region of a linear chromosome
where the 2 sister chromatids join
2. Kinetochore formation: centromere is
the site of assembly of the kinetochore
that attaches to the microtubules of the
mitotic/meiotic spindle. The sister
chromatids are in turn joined via the
centromere to the spindle microtubules.
3. Proper chromosome segregation:
centromeres are essential for the correct
segregation of daughter chromosomes
after DNA replication, so that each copy
goes to each of the 2 daughter cell during
cell division. The presence of only one
centromere on each chromosome is
critical so that each kinetochore binds to
kinetochore spindle fibres and is pulled
towards one pole of the cell during cell
division. In absence of a centromere, the
chromosomes will segregate randomly,
leading to loss of duplication of
chromosomes in daughter cells
 Contains hundreds to as many as 2000
tandem repeats of the sequence 5’ –
TTAGGG – 3’
 3’ end of the G-rich strand extends 12
to 16 nucleotides beyond the 4’ end of
the complementary C-rich strand,
forming a 3’ single-stranded overhang,
which folds back on itself to form a
hairpin loop called telomere loop (tloop)
1. Protective function: the t-loop forms a
cap with telomere-specific proteins that
protect the 5’ ends and 3’ overhangs of
linear chromosomes from degradation
by cellular exonucleases. The unique
structure also protects it from being
recognised by bell’s repair machinery as
a damaged DNA molecule.
2. Maintaining stability: it confers
stability to linear chromosomes as the tloops prevent the chromosome tips
from fusing spontaneously
3. preventing loos of genes: telomeres
protect organism’s genes from being
eroded as the linear chromosome end
shortens with each successive round of
DNA replication due to the endreplication problem, ensuring DNA
replication can occur without loss of
important coding sequences
4. regulating replicative cell senescence:
after the telomeres shorten to a critical
length, the cell reaches Hayflick’s limit
and enters a period of replicative cell
senescence
Action of Telomerase




Telomerase does not prevent the end replication problem; it does not stop the shortening
of chromosomal ends during replication
It only lengthens and thereby maintains, the chromosomal ends after the end replication
problem has occurred
Generally found in stem cells, diploid germline cells and cancer cells
A ribonucleoprotein (protein-RNA) complex that is made up of: RNA sequence template 3’
AAUCCC 5’ that is complementary to the telomere repeat sequence 5’ TTAGGG 3’ &
Telomere Reverse Transcriptase (TERT), a reverse transcriptase enzyme that provides
catalytic action whereby DNA is synthesised from an RNA template
Topic 11-13: Genetic & Molecular Basis for Variation in Cancer
telomerase RNA binds complementarily to the 3' overhang of the parental DNA
strand
telomerase extends the 3' overhang of the parental DNA strand in the 5' to
3' direction by adding sequence repeats of 5' TTAGGG 3' via
complementary base-pairing
by lengthening the 3' overhang, the synthesis of the shorter daughter
strand can be extended during the next round of DNA replication, resulting
in a longer telomere
the action of telomerase thus helps maintain the number of repeats at the
telomerase, delaying the senescence of cells and enabling them to
proliferate indefintely
1. Telomerase enzyme recognises and binds to the G-rich telomere sequence at the 3’
overhang on the parental strand. The 3’ nucleotides are base paired to the 5’ UAA 3’
sequence in the RNA template of the telomerase.
2. Through its reverse transcriptase activity, telomerase adds nucleotides to the 3’ end of the
overhang using the bound RNA as template, thereby extending the 3’ end of the parental
strand. The sequence 5’ GGGTTA 3’ is added one nucleotide at a time.
3. The telomerase is translocated to the end of the extended overhang. The result is that the
telomere is extended in a 5’ to 3’ direction, over repeated cycles of elongation and
translocation.
4. Replication of the incomplete lagging daughter strand is completed by using these
extensions as a template for synthesis of the complementary strand by DNA polymerase,
leaving a 3’ overhang
Topic 11-13: Genetic & Molecular Basis for Variation in Cancer
Gene and Chromosomal Mutations
Gene
Nucleotide
(point)
substitution
mutations
Chromosomal
aberrations
Nucleotide insertion/deletion
In multiples of 3
Not in multiples of 3
Nonsense mutation
Missense mutation
Frameshift Mutation: Extensive
missense mutation
Neutral mutation
Silent mutation
Changes in
Changes in chromosome number
chromosomal
Aneuploidy
Euploidy eg. polyploidy
structure
Deletion
Lose/ gain one or
Autoploidy
more chromosomes (extra set from same species)
Duplication
Inversion
Alloploidy
(extra
set
from
different species)
Translocation
Gene mutation: involves chemical changes that affect the DNA sequence of just one gene; an
alteration to an organism’s characteristics that is inherited, due to a change in the genetic material
of a cell, and it can destroy an organism if it occurs in a vital position in the DNA sequence.
Sickle cell Anaemia

Involves a mutation in the β-globin gene, which encodes one of the polypeptide subunits
that make up haemoglobin.
Genetic and molecular basis:







Single-base substitution of a thymine for an adenine at one position in the haemoglobin
gene which results in a missense mutation
Sixth amino acid residue changed from a glutamate (hydrophilic) to a valine (hydrophobic)
Specific 3D conformation and function of the protein is altered
The substitution creates a hydrophobic spot on the outside of the protein structure that
sticks to the hydrophobic region of an adjacent β chain
Mutant haemoglobin subunits tend to stick to one another when the oxygen
concentration is low, particularly in capillaries and veins
The aggregated proteins form fibre-like structures within the red blood cells
At high oxygen concentration, haemoglobin resumes globular haemoglobin structure
Physiological effects:



Fibre-like structures cause the rbc cells to lose their normal morphology and become
sickle-shaped
Sickle-shaped rbc are less able to move through capillaries and can block blood flow,
resulting in severe pain and cell death of surrounding tissue due to shortage in oxygen
Sickled rbc are also fragile and easily destroyed, further decreasing the oxygen carrying
capacity of blood
Topic 11-13: Genetic & Molecular Basis for Variation in Cancer
Causes of Gene mutations
Spontaneous Mutations
Mutations that occur naturally; may be the result of errors that occur during DNA replication,
recombination or repair
DNA replication and repair
DNA slippage
 DNA polymerase sometimes insert the wrong nucleotide or  Daughter or parental DNA
too many or too few nucleotides into DNA sequence
strand slips during DNA
replication followed by folding
 Some mistakes are corrected immediately during
back of the strand due to
replication through proofreading, and some are corrected
transient dissociation and
after replication in mismatch repair
misaligned reannealing
 During proofreading, DNA polymerase enzymes recognise
 Hence, there is a mispairing
mistakes and replace the incorrectly inserted nucleotide
between the daughter DNA
so that replication can continue
strand and the parental
 After replication, mismatch repair reduces the final error
template strand
rate even further as incorrectly paired nucleotides cause
 This causes parts of the DNA
deformaties in the secondary structure of the final DNA
which are folded back to be
molecule
copied more than once
 During mismatch repair, enzymes recognise and fix these
deformities by removing the incorrectly paired nucleotide  If it corresponds to a gene, it
will result in gene duplication
and replacing it with the correct nucleotide
 Some errors fail to be recognised and are passed down
from one cellular generation to the next
Induced Mutation
Physical agents
Chemical agents
X-rays  Results in the production Base
 Molecular structures that are similar to the
analogues
of free radicals of water
bases normally found in DNA may be
which are chemically
incorporated into DNA in place of the
reactive
normal bases during DNA replication,
hence producing base substitutions
 Free radicals interact with
BaseDNA to produce double
 Modify the chemical structure and
stranded breaks leading to modifying
properties of bases leads to mispairing
agents
chromosomal
during DNA replication and hence base
rearrangements and
substitution
deletions
 Transfer alkyl groups to bases, modifying
their chemical structure
UV-rays  Absorbed by bases of DNA Intercalat-  Flat molecules with multiple ring
ing agents
structures insert themselves (intercalate)
 This may result in the
btw adjacent bases in one or both strands
production of a covalent
of the DNA helix
attachment btw adjacent
pyrimidines in one strand,
 Leads to insertions or deletions during
usually thymine dimmers
DNA synthesis and hence frameshift
mutations
 Or bp substitutions,
insertions and deletions
 These can block
transcription and DNA
replication and are lethal if
not repaired
Topic 11-13: Genetic & Molecular Basis for Variation in Cancer
Molecular Basis of Cancer
Ten Hallmarks of Cancer
1. Genome instability &  Increased rate of accumulation of mutations
mutation
 Instability occurring at the chromosomal level due to accelerated
rate of chromosomal mutations
 Results in gains or losses of whole chromosomes as well as
alterations to chromosome structure eg. Inversions, deletions,
duplication, translocations of larger chromosomal segments
 Instability occurring at the gene level due to faulty repair pathways,
resulting in single nucleotide substitutions, insertions and deletions
2. Sustaining
 Tumour cells are able to proliferate without the presence of
proliferative signalling
extracellular growth factors, unlike normal cells
3. Evading growth
 In normal tissue, stability of cell numbers is maintained by a host of
suppressors
signals and factors inhibiting cell proliferation and differentiation
 In cancer cells, mutations in genes critical for cell cycle control
render the cells insensitive/non-sensitive to the growth-inhibitory
signals
 Results in:
o Loss of anchorage dependence (anchorage-independence
growth)
o Lack of contact inhibition and density-density inhibition
o Tumour cells continue diving after contact with neighbouring
cells, growing over adjacent cells in disordered, multilayered
patterns
4. Resisting cell death
 By evading apoptosis, malignant cells will generally live for an
by apoptosis
indefinite number of cell divisions, provided the right nutrients and
growth factors are present
5. Enabling replicative
 An uncoupling of a cell’s growth programme for signals in its
immortality
environment, leading to excessive cell division is not sufficient for
the formation of cancer
 For a tumour cell population to expand, there needs to be an
additional disruption to the cell replication limit
 Cancer cells express the enzyme telomerase, that adds telomere
repeats sequences to the 3’ ends of DNA, thus escaping Hayflick’s
limit, maintain telomere lengths and develop unlimited replicative
potential
 Enabling them to divide indefinitely, gaining “immortality”
6. Deregulating cellular
 Tumour cells adjust their energy metabolism to consume
energetics
abnormally large amounts of glucose to provide ATP to proliferate
uncontrollably
 Tumour cells also increase the expression of glucose transporters to
ensure an increased uptake of glucose molecules
7. Inducing angiogenesis  Angiogenesis (vascularisation): the process by which new blood
vessels are formed (not an inherent property of most cells in small,
localised tumours)
 To develop into larger, potentially metastatic tumours, a growing
tumour stimulates the formation of new blood vessels that allow for
Topic 11-13: Genetic & Molecular Basis for Variation in Cancer
8. Activating invasion &
metastasis
9. Avoiding immune
destruction
10. Tumour-promoting
inflammation
Characteristics
Nuclear size
N:C ratio
Nuclear shape
an increased blood flow to the tumour, hence supplying nutrients
and oxygen and removing toxic waste products
 Tumour cells release angiogenesis-activating proteins eg. Vascular
endothelial growth factor and fibroblast growth factor that attract
endothelial cells and promote their proliferation, to stimulate the
formation of new blood vessels
 Metastasis: a process where the primary tumours cells invade local
tissues and blood vessels, and establish secondary tumours called
metastases at distant sites
 Ability to metastasise marks its transformation to a malignant
tumour
 Steps:
o Cancer cells invade surrounding tissues and penetrate through
the walls of lymphatic and blood vessel, thereby gaining access to
the bloodstream
o Cancer cells are transported by the circulatory system
throughout the body
o Cancer cells leave the bloodstream and enter particular organs,
where they establish new secondary tumours at distant sites
from the primary tumour
 A small percentage can evade immune destruction by disabling
components of the immune system that have been dispatched to
eliminate them
 When tumour cells swell and lyse, they release cellular contents to
the extracellular environment, which release proinflammatory
signals to attract inflammatory cells
 Inflammatory cells may be tumour promoting as they may:
o Release growth factors, indirectly inducing tumour growth
o Trigger angiogenesis to aid in tumour growth
o Release protein factors that limit cellular death
o Release enzymes to facilitate angiogenesis, invasion and
metastasis
Benign tumour
Small and uniform in all cells
Low
Regular shape that does not vary
between cells
Usually none or just one
Malignant tumour
Large and usually vary between cells
High
Irregular shapes (pleomorphic) that vary
between cells
Nucleolus
Prominent, large and usually >1 to
number
signify extensive protein synthesis
Nucleolus shape Usually round
Irregular shapes
Rate of mitosis Low and few as benign tumour cells High as malignant tumour cells divide
divide less frequently than malignant rapidly
tumour cells
Differentiation Well-differentiated, resembles
Poorly differentiated and does not
parental cells. They will still have
resemble parental cells. Malignant cells
most of the structural features of the may display varying stages of
cells from which they originated
differentiation as de-differentiation may
Topic 11-13: Genetic & Molecular Basis for Variation in Cancer
Tumour
boundary
Treatment
Well-defined. Tumour cells remain
clustered together in a single mass in
a localised region. They grow slowly,
with a well-defined perimeter and
may be surrounded by a layer of
connective tissue
Complete cure can usually be
achieved by removing the mass
surgically
have occurred
Poorly-defined. Tumour cells may or
may not cluster together, as they have
acquired the ability to invade
surrounding tissues and may form
secondary tumours, called metastases,
at distant sites in body
Systemic treatment like radiation or
chemotherapy is required in
conjunction with surgery to ensure
complete eradication of all tumour cells
Causative factors of Cancer:
1. Lifestyle & Diet
a. Cigarette and tobacco smoking: polycylic aromatic hydrocarbon (PAHs) bind to
DNA of cells to form a physical complex known as adduct, causing DNA damage
b. Exposure to carcinogens: charred meat containing heterocyclic amines (HCAs) and
PAHs
2. Radiation Exposure
a. Ionising radiation: form OH radicals in water
b. DNA damaging UVB rays: form Thymine dimers
3. Age: accumulation of mutations
4. Genetic Predisposition: inherited mutant cancer-critical gene
5. Loss of Immunity: loss of T cells to destroy abnormal cells
6. Viral Infections: transforming viruses e.g. Human Papillomavirus (HPV) may lead to cervical
cancer
Oncogene: a gene that encodes for proteins promoting the loss of growth control and the
conversion of a cell to a malignant state.
Cell-cycle Checkpoints: critical control points where stop and go-ahead signals can regulate the
cycle. Help ensure the orderly progression of the cell cycle.
Proto-oncogenes
A family of genes that usually encode gene products promoting normal cell growth.
Function
 Growth factors: external signals that stimulate cells to divide
 Growth factor receptors: membrane proteins that find to GFs
 Protein kinases: enzymes that modify other proteins by chemically adding
phosphate groups to them. The addition of a phosphate group usually results
in the activation of a protein
 Inhibitors of apoptosis: proteins that inhibit the process of apoptosis and
hence result in a reduced rate of cell death
 Transcriptional factors: proteins that bind to DNA to control the rate of
transcription
Topic 11-13: Genetic & Molecular Basis for Variation in Cancer
Gain-in-function
mutation




Much less common than loss-of-function mutations
Confer an abnormal new or enhanced activity of a protein
Acts in a dominant manner
Mutation of either copy of a proto-oncogene to an oncogene is sufficient to
cause abnormal cell proliferation
 Causes genes to gain function, such as being over-expressed, or to encode for
a hyperactive protein
Ras Mutation  Normal: when activated, relays signals from a growth factor receptor to a
gene
series of protein kinases known as the phosphorylation cascade
 Last protein kinase of the signal transduction pathway activates transcription
of genes encoding proteins stimulating the cell cycle
 Activation of ras signalling causes cell proliferation
 Mutated: changes in the 3D conformation of the ras protein, causeing GTP to
remain donded to the ras protein as a ras-GTP complex and thus stay in a
constant “active” state, even in absence of growth factor
 Results in an increase in cell signalling, transcription and consequently
stimulates the cell cycle
Effects
Quantitative change: tumour formation is induced by an increase in the absolute
number of normal ras protein or by its production in inappropriate cell types
Causes:
Translocation or transposition - gene moved to new locus, under new controls
Gene amplification: multiple copies of the gene
Point mutation within a control element: up regulation of transcription
Qualitative change: conversion of proto-oncogene via changes in the nucleotide
sequence which are responsible for the ras protein becoming hyperactive
Causes: point mutation within the gene – hyperactive or degradation-resistant
protein
Tumour Suppressor Genes (tsg)
A family of normal genes that code for proteins to prevent inappropriate cell cycle progression by
suppressing cell growth and proliferation. The loss of such proteins allows a cell to grow and divide in
an uncontrolled fashion.
Function
 Repression of genes that are essential for the continuation of the
cell cycle
 Take part in cell-signalling pathways to inhibit the cell cycle
 Halt cell division if DNA is damaged
 Trigger DNA repair mechanisms, preventing cells from accumulating
DNA damage
 Initiate apoptosis if DNA damage cannot be repaired
 Maintain cell adhesion
Loss-of-function mutation  Defined as one that results in reduced or abolished protein function
 If only one copy is lost, cell cycle activity remains normal, as the
other copy of the gene is still produces the normal gene product
 Both copies of tsg must be mutated so that no functional gene
product can be produced
 Act in a recessive manner
p53 Mutation
 Normal: commonly known as “Guardian of the Genome”
 A transcription factor that bind to DNA to trigger transcription of
genes involved in cell cycle inhibition
Topic 11-13: Genetic & Molecular Basis for Variation in Cancer
 Activated protein binds to specific DNA control elements and
promotes transcription for the relevant genes eg. P21 gene, whose
proteins stop the cell cycle by binding to proteins that are involved
in cell cycle progression eg. Cyclin-dependent kinases
 Ensures that damaged DNA is not replicated and gives time for the
cell to repair the DNA damage
 Concurrently, p53 protein also stimulates DNA repair mechanisms
to rectify the damage
 If damage is irreparable, p53 activate suicide genes to produce
proteins that initiate apoptosis
 Mutant cell becomes able to proliferate uncontrollably and evade
apoptosis
 Genetic instability, characterised by accumulation of further cancerpromoting mutation due to loss of ability to repair DNA
Quantitative change: tumour formation is induced by a decrease in
the absolute number of p53 proteins
Qualitative change: tumour formation is induced by production of
inactivated, non-functional p53 proteins
Consequences
Angiogenesis formation of
new blood
vessles
Accumulation
of mutations
Tumourigenesis:
Activation of
telomerase
Multi-step
model of
cancer
progression
Metastasis acquiring the
capacity to
invade tissues
 Development of a malignant
tumour
 Multi-step process,
characterised by a progression
of permanent alterations in a
single cell lineage
 Tumour cells are clonal
 Selection of tumour cells that
proliferate more aggressively
Accumulation of Mutations



A single mutation is not enough to convert a healthy cell into a cancer cell
Genesis of cancer typically requires several independent mutations in cancer-critical genes in
the lineage of a single cell including both the activation of proto-oncogenes to oncogenes and
inactivation of tumour suppressor genes
Render the cells increasingly less responsive to the body’s normal regulatory machinery and
better able to invade normal tissues
Case Study - Familial Adenomatous Polyposis (FAP)
All required mutations (at 2 tumour suppressor gene mutations and one oncogene) must occur in
a single cell lineage in order for the cancer to develop.
Topic 11-13: Genetic & Molecular Basis for Variation in Cancer
1. Loss of tsg
APC
8. A malignant
carcinoma
develops
2. A polyp
forms on the
colon wall
7. Loss of tsg
p53
3. Activation
of ras gene
6. A class III
benign
adenoma
grows
4. A class II
benign
adenoma
grows
5. Loss of tsg
DCC
9. other
changes; loss
of antimetastasis
gene
Mutation 1: tsg APC gene (controls
proliferation, maturation, cell-tocell contact and growth inhibition)
 Individuals inherit one mutant
copy of APC (adenomatous
10. cancer
polyposis coli) gene located on
metastasises
chromosome 5
 The presence of a heterozygous APC
mutation causes the epithelial cells of the colon to
partially escape cell cycle control, and the cell divides to
form a small cluster of cells called a polyp/ adenoma
 In most cases, the 2nd APC allele becomes mutant in a
later stage of cancer development
Mutation 2: ras gene (proto-oncogene – stimulates cell growth and division by transmitting
growth signals from the cell surface to the nucleus)
 Gain-of-function mutation of the ras proto-oncogene results in it becoming a ras oncogene,
producing a hyperactive ras protein
 Results in the ras protein being permanently activated leading to continual signalling of the cell
cycle to proceed into cell division
 This allows an escape of the cell cycle control and epithelial cells divide uncontrollably
 Combined APC ad ras gene mutations trigger the development of intermediate (class II)
adenomas
 These adenomas have defects in normal cell differentiation and will grow in culture, in absence
of contact with other cells and hence are transformed
Mutation 3: tsg DCC gene (involved in cell adhesion and differentiation)
 Loss of function of both alleles of the DCC gene
 Result in formation of late stage (class III) adenomas with a number of finger-like outgrowths
called villi
Mutation 4: tsg p53 gene (arrests cell cycle in response to DNA damage)
 In order for late adenomas to progress to cancerous adenomas, cells need to lose both
functional copies of p53 genes
 Results in high mutation rates throughout the genome and loss of cell proliferation control
 Accumulation of mutations in an unknown number of genes associated with metastasis leads
to malignancy