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PowerPoint to accompany
Genetics: From Genes to
Genomes
Fourth Edition
Leland H. Hartwell, Leroy Hood,
Michael L. Goldberg, Ann E. Reynolds,
and Lee M. Silver
Prepared by Mary A. Bedell
University of Georgia
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Hartwell et al., 4th edition
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PART V
How Genes Are Regulated
CHAPTER
Somatic Mutation and
the Genetics of Cancer
CHAPTER OUTLINE
 17.1 Overview: Initiation of Division
 17.2 Cancer: A Failure of Control over Cell Division
 17.3 The Normal Control of Cell Division
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The relative percentages of new cancers in the
United States that occur at different sites
Fig. 17.1
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Two unifying themes about cancer genetics
Cancer is a disease of genes
• Multiple cancer phenotypes arise from mutations in
genes that regulate cell growth and division
• Environmental chemicals increase mutation rates and
increase chances of cancer
Cancer has a different inheritance pattern than other genetic
disorders
• Inherited mutations can predispose to cancer, but the
mutations causing cancer occur in somatic cells
• Mutations accumulate in clonal descendants of a
single cell
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Overview of the initiation of cell division
Two basic types of signals that tell cells whether to divide,
metabolize, or die
Extracellular signals – act over long or short distances
• Collectively known as hormones
• Steroids, peptides, or proteins
Cell-bound signals – require direct contact between cells
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An example of an extracellular signal
that acts over large distances
Thyroid-stimulating
hormone (TSH) produced
in pituitary gland
Moves through blood to
thyroid gland, which
expresses thyroxine
Fig. 17.2a
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An example of an extracellular signal that is
mediated by cell-to-cell contact
Fig. 17.2b
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Each signaling system has four components
Growth factors
• Extracellular hormones or cell-bound signals that
stimulate or inhibit cell proliferation
Receptors
• Comprised of a signal-binding site outside the cell, a
transmembrane segment, and an intracellular domain
Signal transducers
• Located in cytoplasm
Transcription factors
• Activate expression of specific genes to either promote
or inhibit cell proliferation
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Hormones transmit signals into cells through
receptors that span the cellular membrane
Fig. 17.3a
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Signaling systems
can stimulate or
inhibit growth
Signal transduction activation or inhibition of
intracellular targets after
binding of growth factor
to its receptor
Fig. 17.3b&c
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RAS is an intracellular signaling molecule
Fig. 17.3d
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Cancer phenotypes result from the
accumulation of mutations
Mutations are in genes controlling proliferation as well as
other processes
• Result in a clone of cells that overgrows normal cells
Cancer phenotypes include:
• Uncontrolled cell growth
• Genomic and karyotypic instability
• Potential for immortality
• Ability to invade and disrupt local and distant tissues
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Phenotypic changes that produce
uncontrolled cell growth
Most normal cells
Autocrine stimulation:
Cancer cells can make
their own stimulatory
signals
a.1
Most normal cells
Loss of contact inhibition:
Many cancer cells
Many cancer cells
a.2
Growth of cancer cells
doesn't stop when the
cells contact each other
Fig. 17.4
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Phenotypic changes that produce
uncontrolled cell growth (cont)
Most normal cells
Loss of cell death:
Cancer cells are more
resistant to programmed
cell death (apoptosis)
Loss of gap junctions:
Many cancer cells
a.3
Most normal cells
Many cancer cells
a.4
Cancer cells lose channels
for communicating with
adjacent cells
Fig. 17.4
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Phenotypic changes that produce
genomic and karyotypic instability
Defects in DNA replication
machinery:
b.1
Cancer cells have lost the ability
to replicate their DNA accurately
Increased mutation rates can
occur because of defects in
DNA replication machinery
Fig. 17.4
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Phenotypic changes that produce
genomic and karyotypic instability (cont)
Increased rate of
chromosomal aberrations:
Cancer cells often have
chromosome rearrangements
(translocations, deletions,
aneuploidy, etc)
Some rearrangements appear
regularly in specific tumor
types
Fig. 17.4b.2
Fig. 17.4b.2
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Phenotypic changes that produce
a potential for immortality
Loss of limitations on the number of cell divisions:
Tumor cells can divide indefinitely in culture (below) and express
telomerase (not shown)
Most normal cells
Many cancer cells
c.1
Immortality
c.2
Growth in
soft agar
Fig. 17.4
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Phenotypic changes that enable a tumor to
disrupt local tissue and invade distant tissues
Ability to metastasize:
Tumor cells can invade
the surrounding tissue
and travel through the
bloodstream
d.1
Angiogenesis:
Tumor cells can secrete
substances that promote
growth of blood vessels
d.2
Fig. 17.4
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Evidence from mouse models that cancer is
caused by several mutations
Transgenic mice with dominant
mutations in the myc gene and
in the ras gene
Mice with recessive mutations
in the p53 gene
(a)
(b)
Fig. 17.5a
Fig. 17.5
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Evidence that cancer cells are clonal
descendants of a single somatic cell
Analysis of polymorphic
enzymes encoded by the X
chromosome in females
Sample from normal tissues
has mixture of both alleles
Clones of normal cells has
only one allele
Sample from tumor has only
one allele
Fig. 17.6
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The incidence of some common cancers
varies between countries
Table 17.1
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The role of environmental mutagens in cancer
Concordance for the same type of cancer in first degree
relatives (i.e. siblings) is low for most forms of cancer
The incidence of some cancers varies between countries
(see Table 17.2)
• When a population migrates to a new location, the
cancer profile becomes like that of the indigenous
population
Numerous environmental agents are mutagens and increase
the likelihood of cancer
• Some viruses, cigarette smoke
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Cancer development over time
Lung cancer death rates and incidence of cancer with age
Fig. 17.7
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Some families have a genetic predisposition
to certain types of cancer
Example: retinoblastoma
caused by mutations in RB
gene
Individuals who inherit one
copy of the RB− allele are
prone to cancer of the retina
During proliferation of retinal
cells, the RB+ allele is lost or
mutated
Tumors develop as a clone
of RB−/RB− cells
Fig. 17.8
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Cancer is thought to arise by successive
mutations in a clone of proliferating cells
Fig. 17.9
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Cancer-producing mutations are
of two general types
Fig. 17.10
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Oncogenes act dominantly and cause
increased proliferation
Oncogenes are produced when mutations cause improper
activation a gene
Two approaches to identifying oncogenes:
• Tumor-causing viruses (Fig 17.11a)
 Many tumor viruses in animals are retroviruses
 Some DNA viruses carry oncogenes [e.g. Human
papillomavirus (HPV)]
• Tumor DNA (Fig. 17.11b)
 Transform normal mouse cells in culture with human tumor
DNA
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Cancer-causing retroviruses carry a mutant or
overexpressed copy of a cellular gene
After infection, retroviral genome integrates into host
genome
If the retrovirus integrates near a proto-oncogene, the protooncogene can be packaged with the viral genome
Fig. 17.11a
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Retroviruses and their associated oncogenes
Table 17.2
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DNA from human tumor
cells is able to transform
normal mouse cells into
tumor cells
Human gene that is oncogenic
can be identified and cloned from
transformed mouse cells
Fig. 17.11b
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The RAS oncogene is the mutant form of the
RAS proto-oncogene
Normal RAS is inactive until it becomes activated by
binding of growth factors to their receptors
Oncogenic forms of RAS are constitutively activated
Fig. 17.11c
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Oncogenes are members of signal
transduction systems
Table 17.3
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Cancer can be caused by mutations that
improperly inactivate tumor suppressor genes
Function of normal allele of tumor suppressor genes is to
control cell proliferation
Mutant tumor suppressor alleles act recessively and cause
increased cell proliferation
Tumor suppressor genes identified through genetic analysis
of families with inherited predisposition to cancer
• Inheritance of a mutant tumor suppressor allele
• One normal allele sufficient for normal cell proliferation
in heterozygotes
• Wild-type allele in somatic cells of heterozygote can be
lost or mutated  abnormal cell proliferation
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The retinoblastoma tumor-suppressor gene
Fig. 17.12
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Mutant alleles of these tumor-suppressor genes
decrease the accuracy of cell reproduction
Table 17.4
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The normal
control of cell
division
Four phases of the cell
cycle:
G1, S, G2, and M
Fig. 17.13
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Experiments with yeast helped identify genes
that control cell division
Two kinds of used: Saccharomyces cerevisiae (budding
yeast) and Schizosaccharomyces pombe (fission yeast)
Usefulness of yeast for studies of the cell cycle
• Both grow as haploids or diploids
 Can identify recessive mutations in haploids
 Can do complementation analysis in diploids
• S. cerevisiae – size of buds serves as a marker of
progress through the cell cycle
 Daughter cells arise as small buds on mother cell at end of
G1 and grow during mitosis
 Stage of cell cycle can be determined by relative
appearance of buds (see Fig 17.14)
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The isolation of temperature-sensitive
mutants of yeast
Mutants grow normally at
permissive temperature (22°)
At restrictive temperature (36°),
mutants lose gene function
After replica plating, colonies that
grow at 22° but not at 36° have
temperature-sensitive mutation
Fig. 17.15
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A temperature-sensitive cell-cycle mutant
in S. cerevesiae
Cells grown at permissive
temperature display buds of all
sizes (asynchronous division)
Growth of the same cells at
restrictive temperature – all
have large buds
Fig. 17.14a
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Fig. 17.14b
39
Some important cell-cycle and
DNA repair genes
Table 17.5
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CDKs interact with cyclins and control the cell
cycle by phosphorylating other proteins
Cyclin-dependent kinases (CDKs) – family of kinases that
regulate the transition from G1 to S and from G2 to M
• Cyclin specifies the protein targets for CDK
Phosphorylation by CDKs can activate or inactive a protein
Fig. 17.16a
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CDKs control the dissolution of the
nuclear membrane at mitosis
Lamins – provide structural support to the nucleus
• Form an insoluble matrix during most of the cell cycle
At mitosis, lamins are phosphorylated by CDKs and become
soluble
Fig. 17.16
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Mutant yeast permit the cloning of
a human CDK gene
Human CDKs and
cyclins can function in
yeast and replace the
corresponding yeast
proteins
Fig. 17.17
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CDKs mediate the transition from the G1 to the
S phase of the cell cycle
Fig. 17.18
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CDK activity in yeast is controlled by
phosphorylation and dephosphorylation
Fig. 17.19
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Cell-cycle checkpoints ensure
genomic stability
Checkpoints monitor the genome and cell-cycle machinery
before allowing progression to the next stage of cell cycle
G1-to-S checkpoint
• DNA synthesis can be delayed to allow time for repair
of DNA that was damaged during G1
The G2-to-M checkpoint
• Mitosis can be delayed to allow time for repair of DNA
that was damaged during G2
Spindle checkpoint
• Monitors formation of mitotic spindle and engagement
of all pairs of sister chromatids
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The G1-to-S checkpoint is activated
by DNA damage
Fig. 17.20a
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Disruption of the G1-to-S checkpoint in
p53-deficient cells can lead to amplified DNA
Tumor cells often have homogenously staining regions
(HSRs) or small, extrachromosomal pieces of DNA (double
minutes)
Fig. 17.20b
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Disruption of the G1-to-S checkpoint in
p53-deficient cells can lead to many types of
chromosome rearrangements
Fig. 17.20c
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Checkpoints acting at the G2-to-M cell-cycle
transition or during M phase
Fig. 17.21
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The necessity of checkpoints
Checkpoints are not essential for cell division
Cells with defective checkpoints are viable and divide at
normal rates
• But, they are much more vulnerable to DNA damage
than normal cells
Checkpoints help prevent transmission of three kinds of
genomic instability (Fig 17.22)
• Chromosome aberrations
• Changes in ploidy
• Aneuploidy
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Three classes of error lead to
aneuploidy in tumor cells
Fig. 17.22a
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Chromosome painting can be used to detect
chromosome rearrangements
Chromosomes from normal
cells
Chromosomes from tumor
cells
Fig. 17.22
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