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Genetics of Cancer
Genetic Mutations that Lead
to Uncontrolled Cell Growth
How do we define cancer?
Cancer is a group of disorders that
causes cells to escape normal controls
on cell division
-cancer cells divide more frequently
-cancer cells divide an unlimited number of
times
-cancer cells are not inhibited by contact with
other cells and can form tumors
-cancer cells can invade other tissues, a
process called metastasis
Non-cancerous
cells form sheets.
Cancer cells
grow into tumors.
Cancer cells can
invade other tissues.
Cancer is the result of a series of
mutations in genes already existing within
the cell. Environmental agents cause a
significant number of these mutations.
Oncogene
Tumor
Suppressor
A series of mutations is responsible for the
development of FAP colon cancer.
Clonal
Evolution
of Tumor
Cells
Cells gain mutations
that increase their
ability to divide and
metastasize
Types of Mutations Causing
Cancer
• Dominant Oncogenic Alleles
– Gain of function mutations
– Dominant allele codes for gene product that
stimulates cell proliferation
– Proto-oncogene undergoes mutation or
comes under alternate control to become
an oncogene (may involve viruses)
– Increased cell division provides an
opportunity to accumulate mutations in
additional genes
Dominant Oncogenic Alleles
Types of Mutations Causing
Cancer
• Recessive Tumor Suppressor Alleles
– Loss of function mutations
– Recessive allele codes for gene
product that fails to inhibit cell
proliferation
– Heterozygous individual is prone to
cancer development when the single
copy of dominant allele is mutated to a
recessive allele
Recessive Tumor Suppressor Alleles
Applying Your Knowledge
TRUE: Thumbs Up
FALSE: Thumbs Down
Indicate whether each statement is TRUE or FALSE
• Cancer cells escape the normal controls on cell
division.
• Oncogenes are recessive mutations.
• The growth of a cancer cell is stopped by
contact with another cell.
• Cancer-causing mutations in tumor suppressor
alleles represent a loss of function.
Control of the Cell Cycle
Mechanisms for controlling progress
through the cell cycle
Extracellular Signals
Control the timing of cell division
Transitions
Orderly progression from one stage of cell
cycle to another
Checkpoints
Delay progression to next stage if cell
must repair damage
Extracellular Signals
Ras is a G-protein that is part
of a signal transduction
pathway to stimulate cell
division, in response to
growth factor binding to a
transmembrane receptor
Extracellular Signals
The normal RAS protein product
is reversibly activated by a signal
from a growth factor and
stimulates cell proliferation only
when active.
The RAS oncogene is
always activated, leading
to uncontrolled growth.
Cell Cycle Transitions and Checkpoints
G2M
Transition
Apoptosis
Checkpoint
G2M
Checkpoint
SG2
Transition
P M
G2
assembly of
components
for division
S
A
T
Mitosis
cytokinesis
G1
chromosomes
replicate
DNA Damage
Checkpoint
Spindle
Assembly
Checkpoint
cytoplasm
doubles
G1S
Transition
G1S
Checkpoint
Proteins Controlling Cell Cycle Transitions
• G1S and G2M Transitions are
controlled by CDK-cyclin complexes
– CDK = cyclin-dependent kinase
• Enzyme that activates or inactivates a target
protein by phosphorylation
– Cyclin
• Protein that accumulates at specific stages of cell
cycle to associate with CDK and specify the
target proteins
• Cyclin levels are controlled
by gene regulation and
protein degradation
Phosphorylation of Rb Protein Mediates the
G1 S Transition
Rb = product of the retinoblastoma gene
E2F = transcription factor
How Do Mutations in Rb
Cause Retinal Cancer?
In heterozygotes, conversion of the Rb+ allele to Rbby mutation leads to uncontrolled growth of retinal cells.
Tumor Suppressor Genes p53 and p21
Control the G1 S Checkpoint
How Do Mutations in p53
Cause Cancer?
In the absence of p53 function,
cells enter S phase despite
breaks in chromosomes. This
can lead to chromosomal
rearrangements.
How Do Mutations in p53
Cause Cancer?
p53 gives an internal
signal for apoptosis
If DNA damage cannot be
repaired, functional p53
protein triggers apoptosis
(programmed cell death).
Mutations in p53 allow
defective cells to proliferate.
Defects in DNA Repair
•BRCA1 is a tumor
suppressor involved
in DNA repair. Faulty
copies of BRCA1
cause inherited breast
cancer.
•The disease Xeroderma
Pigmentosum results
from a defect in
nucleotide excision
repair.
Viral Origin of
Some Cancers
Retroviruses can cause
cancer by mutating or
rearranging host genes
Viral Origin of Some Cancers
Retroviruses can cause cancer by
changing the expression of host genes
Applying Your Knowledge
1.
2.
3.
4.
Dominant Oncogenic Allele
Recessive Tumor Suppressor Allele
CDK-Cyclin Complex
Growth Factor
Which description best represents the
• Cancer-causing allele for Rb protein?
• Extracellular signal for cell division?
• Cancer-causing RAS allele?
• Component that influences cell cycle
progress through phosphorylation of
molecules?