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Chapter 19 Lecture
Concepts of Genetics
Tenth Edition
Cancer and
Regulation of the
Cell Cycle
Cancer is a genetic disease
• Cancer is a genetic disease at the somatic
level resulting from gene products from
mutated or abnormally expressed genes
• Cancer cells share two fundamental
properties:
– unregulated cell proliferation
– metastatic spread
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• Genomic alterations that are associated
with cancer range from single-nucleotide
substitutions to large-scale
chromosomal rearrangements,
amplifications, and deletions
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A) Normal Cell
B) Cancer Cell
See many
translocations, deletions
and aneuploidy in the
cancer karyotype
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Figure 19.1
• Most cancers are somatic, with only 1%
due to germ-line mutations
• Cancers rarely arise from single gene
mutations but from the accumulation of
mutations in many genes (6–12)
• These mutations affect multiple cellular
functions: DNA repair, cell division,
apoptosis, cellular differentiation,
migratory behavior and cell-cell contact
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Cancer is a multistep process requiring
multiple mutations
• Age-related cancer is an indication that
cancer develops from the accumulation of
several mutagenic events in a single cell
– The incidence of most cancers rises
exponentially with age
– Many independent mutations, occurring
randomly and with a low probability, are
necessary before a cell becomes malignant
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© 2012 Pearson Education, Inc.
Figure 19.2
• Cancers develop in progressive steps
beginning with mildly aberrant cells and
progressing to increasingly tumorigenic
and malignant cells
• Each step in tumorigenesis appears to
be the result of one or more genetic
alterations that progressively release the
cell from the normal controls on cell
proliferation and malignancy
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Cancer cells contain genetic defects
affecting cell cycle regulation
• Growth and differentiation of cells are
strictly regulated
• Normal regulation over cell proliferation
involves a large number of gene products
that control steps in the cell cycle
• In cancer cells these are mutated or
aberrantly expressed, leading to
uncontrolled cell proliferation
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• Interphase of the cell cycle is when a cell
grows and replicates its DNA (G1, S, G2)
• Cells that stop proliferating enter G0, in
which they do not grow or divide but are
metabolically active
– Neurons
• Cancer cells are unable to enter G0 and
cycle continuously
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• Signal transduction initiates a program of
gene expression that propels the cell out
of G0 and back into the cell cycle
• Cancer cells often have defects in signal
transduction pathways
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• At the G1/S, G2/M, and M checkpoints, cells
decide whether to proceed to the next stage of the
cell cycle
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• Regulation of cell-cycle progress is mediated by cyclins and
cyclin-dependent kinases (CDKs) that regulate synthesis and
destruction of cyclin proteins
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Control of Apoptosis
• Cells halt progress through the cell cycle if
DNA replication, repair, or chromosome
assembly is aberrant
• If DNA damage is so severe that repair is
impossible, the cell may initiate
apoptosis, or programmed cell death
Prevents cancer
– Also eliminates cells not contributing the final
adult organism
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© 2012 Pearson Education, Inc.
Figure 19.8a
• Proto-oncogenes are genes whose
products promote cell growth and division
These genes encode
– transcription factors that stimulate expression
of other genes
– signal transduction molecules that stimulate
cell division
– cell-cycle regulators that move through the
cell cycle
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• An oncogene is a proto-oncogene that is
mutated and contributes to the
development of cancer
– Gain of function alteration
– Only one allele of the proto-oncogene needs
to be mutated or misexpressed to contribute
to cancer
• Confers a dominant cancer phenotype
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• The products of tumor-suppressor
genes normally regulate cell-cycle
checkpoints and initiate the process of
apoptosis
• When tumor-suppressor genes are
mutated or inactivated, cells are unable to
respond normally to cell-cycle checkpoints
or are unable to undergo apoptosis if DNA
damage is extensive
– Leads to more mutations and development of
cancer
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RB1 tumor-suppressor gene
• Loss or mutation of both alleles of the RB1
tumor-suppressor gene contributes to
the development of many cancers due to
unregulated progression through the cell
cycle
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© 2012 Pearson Education, Inc.
Figure 19.11
• Most cancers result from somatic cell mutations, but 50 forms of
hereditary cancer (1–2%) are known
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• Most inherited cancer-susceptibility alleles
are not sufficient in themselves to trigger
cancer development
• At least one other somatic mutation in the
other copy of the gene must occur to drive
a cell toward tumorigenesis
– Loss of heterozygosity
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• Mutations in other genes are also usually
necessary to fully express the cancer
phenotype
• An example is the development of familial
adenomatous polyposis (FAP)
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© 2012 Pearson Education, Inc.
Figure 19.13