Download Section 16.1 What Is Cancer?

Essentials of GENETICS
Eighth Edition
16
The Genetics
of Cancer
William S. Klug
Michael R. Cummings
Charlotte A. Spencer
Michael A. Palladino
Lecture Presentations by
Kiran Misra
Edinboro University
© 2013 Pearson Education, Inc.
SEM of two prostrate cancer cells in the final
stages of cell division.
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Chapter Contents
16.1
Cancer Is a Genetic Disease at the Level of Somatic
Cells
16.2
Cancer Cells Contain Genetic Defects Affecting
Genomic Stability, DNA Repair, and Chromatin
Modifications
16.3
Cancer Cells Contain Genetic Defects Affecting CellCycle Regulation and Apoptosis
16.4
Proto-oncogenes and Tumor-Suppressor Genes Are
Altered in Cancer Cells
Continued
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Chapter Contents
16.5
Cancer Cells Metastasize and Invade Other Tissues
16.6
Predisposition to Some Cancers Can Be Inherited
16.7
Viruses Contribute to Cancer in Both Humans and
Animals
16.8
Environmental Agents Contribute to Human Cancers
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Introduction
 Cancer is the leading cause of death in Western
countries.
– More than 1 million cases are diagnosed in the
United States each year, and more than 500,000
die from it.
 Cancer is a genetic disease at the somatic level,
characterized by gene products derived from
mutated or abnormally expressed genes.
– Some cancers are inherited, but most are created
within somatic cells that divide and form tumors.
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16.1 Cancer Is a Genetic Disease
at the Level of Somatic Cells
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Section 16.1
 Cancer is a genetic disease
 Genomic alterations associated with cancer
include,
– Single-nucleotide substitutions
– Large-scale chromosome rearrangements,
– Amplifications, and
– Deletions (Figure 16-1).
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Figure 16-1
Karyotype of a
Normal cell
Karyotype of a
cancer cell
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Section 16.1
– Cancer is caused predominantly by mutations in
somatic cells, only1 percent are germ-line mutations.
– Rarely arises from a single mutation but from
accumulation of mutations in many genes
– The mutated genes can affect multiple cellular
functions such as
– repair of damaged DNA,
– cell cycle or cell division,
– apoptosis, etc..
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Section 16.1 What Is Cancer?
 Cancer is a large complex of diseases, up to a
hundred, that behave differently depending on
their cellular type of origin.
 All cancers share two fundamental properties.
– Abnormal cell growth and division (proliferation)
– Defects in normal restraints that prevent cells from
spreading (metastasis)
 It is this combination of cell proliferation and
metastasic spread that makes cancer cells
dangerous.
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Figure 8.9
Proliferation and metastasis of a malignant tumor of
the breast
Lymph
vessels
Blood
vessel
Tumor
Tumor in
another
part of
the body
Glandular
tissue
Growth
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Invasion
Metastasis
Growing out of control, cancer cells produce
malignant tumors
 Cancers are named according to the organ or
tissue in which they originate.
– Carcinomas arise in external or internal body
coverings.
– Sarcomas arise in supportive and connective tissue.
– Leukemias and lymphomas arise from blood-forming
tissues.
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Section 16.1 What Is Cancer?
 In normal cells cell division and spread is tightly
controlled by gene products that are expressed
appropriately in time and space.
 In cancer cells genes controlling above processes
are either mutated or not expressed.
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Section 16.1 What Is Cancer?
 Benign tumors result from unregulated cell growth
forming a multicellular mass that can be removed
by surgery, causing no serious harm.
 Tumor cells that gain the ability to break loose,
enter the blood stream and metastasize become
Malignant tumors.
– Malignant tumors are difficult to treat and may
become life threatening.
– May contain billions of cells
– May invade and grow in numerous body parts
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Section 16.1 The Clonal Origin of Cancer Cells
 All cancer cells in primary and secondary tumors are
clonal, meaning that they originated from a common
ancestral cell that accumulated numerous specific
mutations.
 Eg: Specific reciprocal chromosomal translocations
are characteristic of many cancers.
– Leukemias and lymphomas (involve white blood cells)
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Section 16.1 The Clonal Origin of Cancer Cells
 Burkitt’s lymphoma shows reciprocal
translocations between chromosome 8 and
chromosomes 2, 14, or 22.
– All cancer cells arise from a single cell that is
passed to progeny.
 X-chromosome inactivation occurs early in
development and occurs at random.
– All cancer cells within a tumor, both primary and
metastatic, within one female individual contain the
same inactivated X chromosome.
– All cancer cells arose from a common ancestral cell.
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Section 16.1 The Cancer Stem Cell Hypothesis
 Many scientists now believe that tumors are
composed of a mixture of cells, many of which do
not proliferate.
 Cancer stem cell hypothesis: Tumor cells that
proliferate give rise to cancer stem cells that have
the capacity for self-renewal.
– The stem cell divides unevenly, creating one
daughter cell that becomes a mature cell type
and one that remains a stem cell.
 Contrasts the theory that every tumor cell has the
potential to form a new tumor.
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Section 16.1 The Cancer Stem Cell Hypothesis
 Evidence is accumulating that cancer stem cells do
exist and have been identified in
– leukemia.
– brain cancer.
– breast cancer.
– colon cancer.
– ovarian cancer.
– pancreatic cancer.
– prostate cancer.
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Section 16.1 The Cancer Stem Cell Hypothesis
 Scientists are not sure about the origin of the cancer
cells:
1.It is possible they may arise from normal adult stem
cells within a tissue
2.Or they may be created from more differentiated cells
that acquire properties similar to stem cells due to the
mutations in genes.
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Section 16.1 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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Section 16.1 Cancer is a multistep process
requiring multiple mutations
 Another indication that cancer is a multistep process
is the delay that occurs between exposure to
carcinogens and the appearance of the cancer.
– An incubation period of five to eight years separated
exposure to radiation from atomic explosions at
Hiroshima and Nagasaki and the onset of leukemia.
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Section 16.1 Cancer is a multistep process
requiring multiple mutations
 Cancers develop in progressive steps beginning
with mildly aberrant cells and progressing to cells
that are increasingly tumorigenic and malignant.
 Each step in tumorigenesis appears to be the
result of two or more genetic alterations that
progressively release the cell from the normal
controls on cell proliferation and malignancy.
– The progressive genetic alterations that create a
cancer cell confer selective advantages to the cell
and are propagated through cell divisions during
the creation of tumors.
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Section 16.1 Cancer is a multistep process
requiring multiple mutations
 Tens of thousands of somatic mutations are present
in cancer cells.
– Of these mutations only Driver mutations give
growth advantage to tumor cells.
 The presence of fewer than a dozen mutated genes
may be sufficient to create a cancer cell.
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16.2 Cancer Cells Contain Genetic Defects
Affecting Genomic Stability, DNA Repair,
and Chromatin Modifications
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Section 16.2 Cancer Cells Contain Genetic Defects
 Cancer cells show higher than normal rates of
– mutation.
– chromosomal abnormalities.
– genomic instability.
 The fundamental defect in cancer cells is a
derangement of the cell’s ability to repair DNA
damage.
 The high level of genomic instability in cancer cells
is known as the mutator phenotype.
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Section 16.2 Genomic Instability and Defective
DNA Repair
 The genomic instability in cancer cells manifests
itself in gross defects such as
– translocations.
– aneuploidy.
– chromosome loss.
– DNA amplification.
– chromosomal deletions (Figures 16-1 and 16-2).
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Figure 16-2
DNA Amplification in neuroblastoma cells:
Two cancer genes are amplified as small DNA fragments
separate from chromosomes.
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Section 16.2 Genomic Instability and Defective
DNA Repair
 Often cancers show specific chromosomal defects
that are used to diagnose the type and stage of the
cancer.
– Chronic myelogenous leukemia (CML)
– The C-ABL gene on chromosome 9 is translocated into
the BCR gene on chromosome 22.
– This structure is known as the Philadelphia
chromosome (Figure 16-3).
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Figure 16-3
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Section 16.2 Chronic myelogenous leukemia (CML)
 The normal C-ABL gene codes for a protein kinase
that acts within signal transduction pathways,
transferring growth factor signals from outside the cell
to the nucleus.
 The BCR-ABL hybrid protein is an abnormal signal
transduction molecule in CML cells that stimulate cell
proliferation even in the absence of external growth
signals.
 Drug that blocks the action of the abnormal protein is
developed. This drug (Gleevac) controls the protein’s
activity that WBCs are no longer produced in an
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Section 16.2 Chromatin Modifications and
Cancer Epigenetics
 Epigenetics is the study of factors that affect gene
expression but do not alter the nucleotide sequence
of the DNA.
– DNA methylation
– Histone acetylation and deacetylation
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Section 16.2 Cancer Epigenetics
 Cancer cells are generally less methylated than
normal cells (hypomethylation).
 However, the promoters of some genes can be
hypermethylated.
 Histone modifications are disrupted in cancer
cells.
– Genes that encode histone-modifying enzymes are
often mutated or aberrantly expressed in cancer
cells.
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Section 16.2 Cancer Epigenetics
 Methylation generally suppresses expression by
transcriptional repression, turning off genes.
 Hypomethylation can release the transcriptional
repression turning on many genes that were
previously turned off.
 Hypermethylation of the tumor suppressor genes
such as those that repair DNA damage and control
cell cycle leads to their repression (turning off
genes that were previously turned on).
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16.3 Cancer Cells Contain Genetic Defects
Affecting Cell-Cycle Regulation and Apoptosis
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Section 16.3
 One of the fundamental aberrations in all cancer cells
is a loss of control over cell proliferation.
 In multicellular organisms, normal cell division
replaces dead and damaged tissue, and this process
is strictly regulated.
 In normal cells large number of gene products control
– Steps in the cell cycle
– Programmed cell death, and
– Response to external growth factors
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Section 16.3 The Cell Cycle and Signal
Transduction
 The cell cycle includes a sequence of events from
one cell division to the next (Figure 16-4).
 Most differentiated cells in multicellular organisms
can remain in the G0 phases (quiescent) indefinitely
but cancer cells are unable to enter G0 and
continuously cycle.
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Figure 16-4
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Section 16.3 Cell-Cycle Control and Checkpoints
 The cell cycle is tightly regulated, and each step
must be completed before entering the next.
 Three distinct check points in the cell cycle
monitor external signals and internal equilibrium
before proceeding to the next stage.
– G1/S,
– G2/M, and
– M checkpoints
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Section 16.3 Cell-Cycle Control and Checkpoints
 G1/S checkpoints monitor cell size and determine
whether DNA has been damaged.
 G2/M is where physiological conditions are checked
(once G1/S are passed) prior to mitosis.
 M: The formation of the spindle-fiber system and
the attachment of spindle fibers to the kinetochores
associated with the centromeres are monitored.
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Figure 8.8B
Growth
factor
EXTRACELLULAR FLUID
Plasma membrane
Relay proteins
Receptor
protein
Signal
transduction
pathway
G1
checkpoint
G1
S
Control
system
M
G2
CYTOPLASM
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Section 16.3 Cell-Cycle Control by Growth
Factors
 External growth signals can stimulate G0 cells to
reenter the cell cycle.
– Signals are delivered by molecules such as growth
factors and hormones that bind to cell surface
receptors. Eg: Endotheilial growth factor
 The process of transmitting growth signals from external
environments to the nucleus is called signal
transduction.
– The process initiates a program of gene expression,
stimulating G0 cells back into the cell cycle.
– Cancer cells have defective signal transduction pathways,
and malignant cells may not respond to external growth
signals.
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Section 16.3
 Mutation or mis-expression of any of the genes
controlling the cell cycle can contribute to the
development of cancer.
 Mutated genes controlling G1/S or G2/M checkpoints
or those controlling cyclins may allow cells to
continue to grow and divide without repairing DNA
damage.
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Section 16.3 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 genetically
controlled apoptosis, or programmed cell death.
– Prevents cancer
– Also eliminates cells not contributing the final adult
organism
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Section 16.3
 The steps in apoptosis are
– fragmentation of nuclear envelope & DNA.
– disruption of internal cellular structures.
– dissolution of cells into small, spherical apoptotic
bodies.
– engulfing of the apoptotic bodies by phagocytic cells.
 Apoptosis reduces the number of mutations passed
to the next generation.
– The same genes controlling the cell cycle also initiate
apoptosis. Disruption of these genes prevent DNA
repair and apoptosis.
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16.4 Proto-oncogenes and Tumor-Suppressor
Genes Are Altered in Cancer Cells
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Section 16.4 Proto-oncogenes and TumorSuppressor Genes
 Two general categories of cancer-causing genes are
mutated or misexpressed in cancer cells.
– Proto-oncogenes and
– Tumor-suppressor genes
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Section 16.4 Proto-oncogenes
 Proto-oncogenes are normal 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 the cell through the cell
cycle.
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Table 16.1
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Section 16.4 Mutations in Proto-oncogenes result
in Oncogenes
 In cancer cells, one or more proto-oncogenes are
altered in such a way that their activities cannot be
controlled in a normal fashion.
– This is due to a mutation in the proto-oncogenes,
resulting in a protein that acts abnormally.
– In other cases, proto-oncogenes are overexpressed
or expressed at an incorrect time.
 When a proto-oncogene is mutated or aberrantly
expressed and contributes to cancer, it is known as
an oncogene.
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Figure 11.16A
Proto-oncogene
(for a protein that stimulates cell division)
DNA
A mutation within
the gene
Multiple copies
of the gene
Oncogene
Hyperactive
growthstimulating
protein in a
normal amount
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The gene is moved to
a new DNA locus,
under new controls
New promoter
Normal growthstimulating
protein
in excess
Normal growthstimulating
protein
in excess
Section 16.4 Mutations in Proto-oncogenes result
in Oncogenes
 An oncogene (a cancer-causing gene) is a mutated
or aberrantly expressed proto-oncogene, a gain-offunction alteration.
– Only one allele of the proto-oncogene needs to
mutate or be misexpressed in order to trigger
uncontrolled growth.
– Oncogenes confer a dominant cancer phenotype.
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Section 16.4 The ras Proto-oncogenes
 The ras genes are mutated in more than 30
percent of human tumors and encode signal
transduction molecules that are associated with the
cell membrane and regulate cell growth and
division.
 Ras proteins transmit signals from the cell
membrane to the nucleus, stimulating cell division.
 Alternate between active and inactive state
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Section 16.4 The ras Proto-oncogenes
 Mutations that convert the ras proto-oncogene to
an oncogene freeze the ras protein into its active
(“on”) conformation, constantly stimulating the
cell to divide, even in the absence of growth factors.
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Section 16.4 Tumor-suppressor genes
 In cells with severe DNA damage, products of tumorsuppressor genes regulate
– cell-cycle checkpoints or
– initiate the process of apoptosis.
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Section 16.4 Tumor-suppressor genes
 In response to DNA damage or growth-suppression
signals from the extracellular, tumor-suppressor genes
produce proteins that halt progress through the cell
cycle.
 Mutated or inactivated tumor-suppressor genes are
unable to respond normally to cell-cycle checkpoints or
are unable to undergo programmed cell death if DNA is
extensive.
 Inactivation of both tumor-suppressive alleles keeps
the cell growing and dividing and may become
tumorigenic.
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Section 16.4 The p53 Tumor-Suppressor Gene
 The p53 tumor-suppressor gene, mutated in
more than 50 percent of all cancers,
 p53 gene encodes a nuclear protein that acts as a
transcription factor repressing or stimulating
transcription of more than 50 different genes.
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Figure 11.16B
Tumor-suppressor gene
Normal
growthinhibiting
protein
Cell division
under control
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Mutated tumor-suppressor gene
Defective,
nonfunctioning
protein
Cell division
not under control
Section 16.4 p53: Guardian of the genome
 In normal cells p53 protein is continuously
synthesized but rapidly degraded, and thus is
present at low levels.
 The p53 protein becomes more stable and
transcriptionally active in response to:
– Chemical damage to DNA
– Double-stranded breaks in DNA by ionizing radiation
– DNA-repair intermediates generated by UV light
exposure increases
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Section 16.4 p53: Guardian of the genome
 The p53 protein initiates two different responses to
DNA damage.
– Arrest cell cycle followed by DNA repair, or
– Apoptosis and cell death if damage can’t be repaired
 p53 acts as a transcription factor to stimulate or
repress the expression of genes involved in each of
the above responses.
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Section 16.4 p53: Guardian of the genome
 Normal cells: p53 arrests the cell cycle at G1/S and
G2/M checkpoints and retards the progression through
the S phase.
– Inhibits cyclin/CDK complexes and regulates the
transcription of other genes involved
 Activated p53 instructs damaged cells to commit
suicide by apoptosis.
– p53 activates the transcription of genes whose products
control this process.
– In cancer cells that lack functional p53, gene products are
not synthesized and apoptosis doesn’t occur.
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Section 16.4 p53: Guardian of the genome
 Cells lacking functional p53 have high mutation
rates and accumulate the types of mutations that
lead to cancer.
 p53 is important for genomic integrity and is referred
to as the “guardian of the genome.”
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Section 16.4 The RB1 Tumor-Suppressor Gene
 Loss or mutation of both alleles of the RB1
(retinoblastoma 1) tumor-suppressor gene
contributes to the development of many cancers due
to unregulated progression through the cell cycle.
– Breast, bone, lung, and bladder cancers
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16.5 Cancer Cells Metastasize and
Invade Other Tissues
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Section 16.5
 To metastasize from the primary tumor, cancer
cells must digest components of the extracellular
matrix and basal lamina, which normally separate
the body’s tissues and thus inhibit migration of cells.
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Section 16.5
 Once cancer cells have disengaged, they enter the
blood or lymphatic system to invade surrounding
tissue, and to develop into secondary tumors.
– Only about 0.01 percent of metastatic cells become
metastatic tumors.
 Metastasis is controlled by a large number of genes,
including those that encode cell-adhesion
molecules, cytoskeleton regulators, and proteolytic
enzymes.
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Section 16.5
 Like tumor-suppressor genes that are mutated in
primary cancers, metastasis-suppressor genes
are mutated or disrupted in metastatic tumors.
 The expression of these genes is reduced by
epigenetic mechanisms rather than by mutation.
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16.6 Predisposition to Some
Cancers Can Be Inherited
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Section 16.6 Inherited predisposition to cancer
 Most cancers result from somatic cell mutations, but
50 forms of hereditary cancer (1–2 percent) are
known (Table 16.2).
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Table 16.2
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Section 16.6 Inherited predisposition to cancer
 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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Section 16.6 Inherited predisposition to cancer
 Mutations in other genes are also usually
necessary to fully express the cancer phenotype.
– Other proto-oncogenes and tumor-suppressor genes
 Thus inherited mutations in one allele of a gene
contributes only one step in a multistep pathway
leading to malignancy.
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Section 16.6 Inherited form of colon cancer
 In familial adenomatous polyposis (FAP) individuals
inherit one mutant copy of the APC (adenomatous
polyposis) gene whose product acts as a tumor
suppressor controlling cell–cell contact and growth
inhibition.
 FAP results from one mutant copy of the APC gene
(chromosome 5, deletions frameshift, and point
mutations).
– Heterozygous APC mutation causes formation of hundreds
to thousands of rectal polyps or adenomas in early life.
– A second APC mutation leads to later stage of cancer
(Figure 16-7).
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Section 16.6
 The second mutation in polyp cells that contain an APC
gene occurs in the ras proto-oncogene which, brings
about the development of intermediate adenomas.
– Cells grown in culture are not growth-inhibited by contact
with other cells (transformation).
 The loss of function of both alleles of the DCC gene
results in the formation of late-stage adenomas, which
then progresses to cancerous adenomas (Ioss of p53
function).
– The final step toward malignancy involves loss of genes
associated with metastasis.
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Figure 16-7
A model for multistep development of colon cancer
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Figure 11.17A
Stepwise development of a typical colon cancer
An oncogene A tumor-suppressor
DNA
changes: is activated gene is inactivated
A second tumorsuppressor gene
is inactivated
Cellular
Increased
changes: cell division
1
Growth of a
malignant tumor
3
Colon wall
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Growth of a polyp
2
Figure 11.17B
Accumulation of mutations in the development
of a cancer cell
1
Chromosomes mutation
Normal
cell
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2
mutations
3
4
mutations mutations
Malignant
cell
16.7 Viruses Contribute to Cancer
in Both Humans and Animals
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Section 16.7 Viruses Contribute to Cancer
 Fifteen percent of human cancers are associated
with viruses, the second greatest risk of cancer
next to tobacco smoke (Table 16.3).
 Retroviruses (RNA virus) can contribute to the
development of cancer in animals and humans.
 Retroviruses integrate into the host genome as
a provirus that is replicated with the host’s DNA
during the normal cell cycle.
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Table 16.3
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Section 16.7
 A retrovirus can cause cancer by integrating near a
proto-oncogene or by integrating a copy of a host
proto-oncogene into its genome.
 The RNA genome of the virus is copied into DNA
by the reverse transcriptase enzyme, which is
brought into the cell by the infecting virus.
– The DNA copy enters the host-cell DNA and integrates
at random.
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Section 16.7
 The integrated DNA copy is called a provirus and
gets replicated along with the host DNA.
 A retrovirus may not kill a cell but may continue to
use it as a factory to replicate more viruses that will
then infect surrounding cells.
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16.8 Environmental Agents
Contribute to Human Cancers
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Section 16.8 Environmental Agents
 Any substance or event that damages DNA has the
potential to be carcinogenic if it causes mutations
to occur in proto-oncogenes or tumor-suppressor
genes, which lead to abnormal replication of the cell
cycle or disruption of controls over apoptosis or
metastasis.
 Carcinogens, both natural and human-made,
include chemicals, radiation, some viruses, and
chronic infections.
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Section 16.8 Environmental Agents
 The most significant environmental carcinogen is
tobacco smoke, which contains at least 60
mutagenic chemicals.
– 30 percent of human cancer deaths are associated
with cigarette smoking.
 Consumption of red meat and animal fat is
associated with colon, prostate, and breast cancer.
 Alcohol may cause inflammation and lead to liver
cancer.
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Section 16.8 Environmental Agents
 Some natural substances and natural processes are
potentially carcinogenic.
 Mold on bread and corn, aflatoxin, is one of the
most carcinogenic chemicals known.
 Naturally occurring nitrosamines, used as meat
preservative, are known to cause cancer.
 Naturally occurring pesticides and antibiotics in
plants can be carcinogenic but do not diminish the
serious cancer risk upon exposure to synthetic
pesticides or asbestos.
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Section 16.8 Environmental Agents
 Natural radiation (UV light, X rays), natural dietary
substances, and substances in the external
environment can cause DNA lesions, producing
mutations that lead to cancer.
 Natural metabolism creates oxidative end products
that can damage DNA, proteins, and lipids.
 Daily, the human body suffers about 10,000 lesions
due to the actions of oxygen free radicals.
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Section 16.8
 When DNA repair enzymes miss these damages,
they become permanent mutations.
 Substances such as growth factors or hormones
that stimulate cell division are ultimately
mutagenic and carcinogenic.
 Chronic inflammation due to infection can result in
accumulation of DNA lesions during tissue repair
and cellular replication.
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