Download Brooker Chapter 22

MEDICAL GENETICS
CANCER
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AND
INTRODUCTION


Our genes underlie every aspect of human health,
both in function and dysfunction
Knowledge of how genes work together and interact
with the environment is very important



It will have a profound impact on the way many diseases
are diagnosed, treated and prevented
It will bring about revolutionary changes in medicine
Indeed, such changes are already beginning

Currently, several hundred genetic tests are in clinical use


E.g., sickle-cell anemia, Huntington disease, cystic fibrosis
Genetic tests are also available to detect predisposition to
certain forms of cancer
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22-2
INTRODUCTION

Approximately 4,000 genetic diseases afflict people


Many of these are the direct result of a mutation in one
gene
Genes also play roles in the development of

Diseases that have a complex pattern of inheritance

E.g., Diabetes, asthma, mental illness

Cancer

Unraveling the complexities of these diseases will be a
challenge for some time to come
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22-3
22.1 GENETIC ANALYSIS OF
HUMAN DISEASES

The study of human genetic diseases provides
insights regarding our traits


E.g., By analyzing people with hemophilia, researchers
have identified genes that participate in blood clotting
Thousands of human diseases have a genetic basis

This section focuses on the diseases that result from
defects in single genes

The mutant genes that cause these diseases often obey simple
Mendelian inheritance patterns
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22-4
Observations of Human Diseases

For traits and diseases, geneticists want to know the
relative contributions from genetics and environment

Geneticists cannot conduct human crosses to
elucidate the genetic basis for diseases


Instead, they must rely on analyses of families that already
exist
Several observations are consistent with the idea
that a disease is caused, at least in part, by genes
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22-5

1. When an individual exhibits a disease, the disorder is more
likely to occur in blood relatives than in the general population

2. Identical twins share the disease more often than fraternal
twins

Identical twins are also called monozygotic twins


Fraternal twins are also called dizygotic twins


They are formed from separate pairs of sperm and egg
Geneticists evaluate the concordance of a disorder, which is the
degree to which it is inherited


They are formed from the same sperm and egg
Concordance refers to the percentage of twin pairs in which both twins
exhibit the disorder or trait
3. The disease does not spread to individuals sharing similar
environmental situations
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22-6

4. Different populations tend to have different frequencies of
the disease

5. The disease tends to develop at a characteristic age


Many genetic disorders exhibit a specific age of onset
6. The human disorder may resemble a genetic disorder that
is already known to have a genetic basis in an animal

Refer to Figure 22.1

7. A correlation is observed between a disease and a mutant
human gene or a chromosomal alteration

If a disease correlates with several of these 7 observations, it
is very likely that the disease has a genetic basis
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22-7
Pedigree Analysis

The pattern of inheritance of monogenic disorders,
can be deduced by analyzing human pedigrees

To use this method, a geneticist must obtain data
from large pedigrees with many affected individuals

In this section, we will examine a few large pedigrees
that involve diseases inherited in different ways

But first, let’s review Figure 2.10
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22-8
Figure 2.10
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
Tay-Sachs Disease (TSD)

Affected individuals appear healthy at birth, but then
develop neurodegenerative symptoms at 4 to 6 months




Cerebral degeneration, blindness and loss of motor function
TSD patients typically die at 3 or 4 years of age
TSD is about 100 times more frequent in Ashkenazi
(eastern Europe) Jewish populations than in others
TSD is the result of a mutation in the gene that encodes
the enzyme hexosaminidase A (Hex A)

HexA breaks down a category of lipids called GM2 gangliosides

An excessive accumulation of this lipid in cells of the CNS
causes the neurodegenerative symptoms

TSD is inherited in an autosomal recessive manner
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22-10
Figure 22.2 A family pedigree of Tay-Sachs disease
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
Four common features of autosomal recessive
inheritance are as follows:

1. Frequently, an affected offspring will have two
unaffected parents

2. When two unaffected heterozygotes have children, the
percentage of affected children is (on average) 25%

3. Two affected individuals will have 100% affected
children

4. The trait occurs with the same frequency in both sexes
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22-12

Disorders that involve defective enzymes typically
have an autosomal recessive mode of inheritance

The heterozygote carrier has 50% of the normal enzyme


Hundreds of genetic diseases are inherited this way


This is sufficient for a normal phenotype
In many cases, the mutant genes responsible have been
clone and mapped
Refer to Table 22.1
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22-13
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22-14

Huntington Disease (HD)



The major symptom of the disease is the degeneration of
certain types of neuron in the brain
This leads to personality changes, dementia and early
death (usually in middle age)
HD is the result of a mutation in a gene that encodes a
protein termed huntingtin

The mutation adds a polyglutamine tract to the protein

This causes an aggregation of the protein in neurons

HD is inherited in an autosomal dominant manner
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22-15
Figure 22.3 A family pedigree of Huntington disease
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
Five common features of autosomal dominant
inheritance are as follows:

1. An affected offspring usually has one or both affected
parents

2. An affected individual, with only one affected parent, is
expected to produce (on average) 50% affected offspring

3. Two affected, heterozygous will have (on average)
25% unaffected offspring

4. The trait occurs with the same frequency in both sexes

5. For most dominant disease-casing alleles, the
homozygote is more severely affected with the disorder
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22-17

Disorders that involve alteration in structural proteins
typically have an autosomal dominant mode of
inheritance

The heterozygote has 50% of the normal protein


Numerous genetic diseases are inherited this way


This is not sufficient for a normal phenotype
In many cases, the mutant genes responsible have been
clone and mapped
Refer to Table 22.2
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22-18
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22-19

A third mode of inheritance is X-linked recessive
inheritance

This type of inheritance poses a special problems for
males

Males have only a
single copy of most
X-linked genes


They are termed
hemizygous
Therefore a female
heterozygous for an
X-linked recessive
gene will pass this
trait to half her sons
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22-20

Hemophilia




The major symptom of the disease is that the blood cannot
clot properly when a wound occurs
For hemophiliacs, common accidental injuries pose a
threat of severe internal or external bleeding
Hemophilia A (also called classical hemophilia) is caused
by a defect in an X-linked gene that encodes the clotting
factor VIII
This disease has also been called the “Royal disease”,
because it has affected many members of European royal
families
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22-21
Figure 22.4
The inheritance pattern of hemophilia A in the royal families of Europe
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

Three common features of X-linked recessive
inheritance are as follows:

1. Males are much more likely to exhibit the trait

2. The mothers of affected males often have brothers or
fathers who are affected with the same trait

3. The daughters of affected males will produce (on
average) 50% affected sons
Refer to Table 22.3 for a few examples
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22-23
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22-24
Many Genetic Disorders are
Heterogeneous

Heterogeneity refers to the phenomenon that a
disease is caused by mutations in different genes

Consider the disease hemophilia



Blood clotting involves a cellular cascade that involved
several different proteins
Therefore, a defect in any of these proteins can cause the
disease
Hemophilia B is caused by a defect in the clotting factor IX

It is also an X-linked recessive disorder
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22-25

Another mechanism that may lead to genetic
heterogeneity occurs when proteins are composed
of many different subunits

Consider the disease thalassemia

This potentially life-threatening disease involves defects
in hemoglobin


a-thalassemia


The defect is in the a-globin subunit
b-thalassemia


Hemoglobin is a tetrameric protein, composed of two a and two b chains
The defect is in the b-globin subunit
Unfortunately, heterogeneity can greatly confound
pedigree analysis
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22-26
Genetic Testing

Genetic testing refers to the use of tests to discover
if an individual has a genetic abnormality

Genetic screening refers to population-wide
genetics testing

Refer to Table 22.4 for examples of testing methods
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
In many cases, single-gene mutations that affect
proteins, can be examined at the protein level

Biochemical assays may be available for enzymes

Consider Tay-Sachs disease (TSD)


An enzymatic assays exist to test for the enzyme HexA
The artificial substrate 4-methylumbellifreone (MU) is covalently
linked to N-acetylglucosamine (GlcNAc)
MU–GlcNAc
(nonfluorescent)



HexA
MU
+
(fluorescent)
GlcNAc
Individuals that are homozygous for the normal allele, produce a
high level of fluorescence
Those that are affected with TSD produce little fluorescence
Heterozygotes produce intermediate levels of fluorescence
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22-29

An alternative approach is to detect single-gene
mutations at the DNA level



Researchers must have previously identified the mutant
gene using molecular techniques
E.g., Duchenne muscular dystrophy, Huntington disease
The most common class of human genetic
abnormality is the change in chromosome number



Most of these result in spontaneous abortions
However, about 1 in 200 live births are aneuploid or have
unbalanced chromosomal alterations
Chromosomal abnormalities can be detected with a
karyotype
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22-30

In the U.S., genetic screening for certain disorders
has become common medical practice

For example



Pregnant women over 35 years of age are screened routinely to
see if they are carriers of chromosomal abnormalities
Widespread screening for phenylketonuria
Genetic testing has also been conducted on specific
population in which a genetic disease is prevalent

E.g., Tay-Sachs disease in the Aschenazi Jews
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22-31

Genetic testing can be performed prior to birth

There are two main types of procedures

1. Amniocentesis


2. Chorionic villi sampling




Fetal cells are obtained from the amniotic fluid
Fetal cells are obtained from the chorion (fetal part of the
placenta)
Can be performed earlier during pregnancy than
amniocentesis
However, it poses a slightly greater risk of miscarriage
Refer to Figure 22.5
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22-32
Figure 22.5
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
Genetic testing and screening are medical practices
with many social and ethical dimensions


Do people have the right to know about their genetic
makeup?
Does it do more harm than good?

Another issue is privacy

In this century we will become more aware of our
genetic makeup and the causes of genetic diseases

It will be necessary therefore, to establish guidelines for
the uses of genetic testing

This may be easier said than done!
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22-34
Prions

Prions are proteinaceous infectious particles

The term was coined by Stanley Prusiner in 1982

Prusiner was the first to propose that prions act as
infectious agents composed entirely of proteins

Prions cause several types of neurodegenerative
diseases of humans and livestock

Refer to Table 22.5
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
Prion-related diseases arise from the ability of the
prion protein to exist in two conformational states:

Normal form, designated PrPC


Does not cause disease
Abnormal form, designated PrPSc

Does cause disease

The gene encoding the prion protein is expressed at
low levels in certain cell types, such as nerve cells

The abnormal protein can come from two sources


1. By “infection” through direct contact or consumption of
contaminated meat
2. By “inheritance”

Some alleles of the PrP gene cause the spontaneous conversion of
PrPC into PrPSc
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22-37
Figure 22.6 A proposed
molecular mechanism of
prion diseases
22-38
PrPSc proteins are deposited as
dense aggregates in the cells of
the brain and peripheral
nervous tissues
PrPSc proteins are also excreted
from infected cells and taken up
by the bloodstream
Thus, a prion disease can
spread throughout the body,
just like many viral diseases
Figure 22.6 A proposed
molecular mechanism of
prion diseases
22-39
22.2 GENETIC BASIS OF
CANCER

Cancer is a disease characterized by uncontrolled
cell division

It is a genetic disease at the cellular level

More than 100 kinds of human cancers are known

These are classified according to the type of cell that has
become cancerous
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22-40

Cancer characteristics

1. Most cancers originate in a single cell


2. At the cellular and genetic levels, cancer is usually a
multistep process




In this regard, a cancerous growth can be considered to be clonal
It begins with a precancerous genetic change (i.e., a benign
growth)
Following additional genetic changes, it progresses to cancerous
cell growth
Refer to Figure 22.7
3. Once a cellular growth has become malignant, the cells
are invasive (i.e., they can invade healthy tissues)

They are also metastatic (i.e., they can migrate to other parts of the
body)
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22-41
Figure 22.7 Progression of
cellular growth leading to
cancer
22-42

~ 1 million Americans are diagnosed with cancer
each year



About 500,000 will die from the disease
5-10% of cancers are inherited
90-95% are not


A small subset of these is the result of spontaneous
mutations and viruses
However, at least 80% of cancers are related to exposure
to mutagens


These alter the structure and expression of genes
An environmental agent that causes cancer is termed a
carcinogen
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22-43
Certain Viruses Can Cause Cancer

A few viruses are known to cause cancer in plants,
animals and humans

Many of these viruses can also infect lab-grown cells and
convert them into malignant cells

The process of converting a normal cell into a
malignant cell is termed transformation

Most cancer-causing viruses are not very potent at
inducing cancer

In addition, most viruses are inefficient at transforming or
are unable to transform normal cells grown in the lab
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22-44

A few types of viruses can rapidly induce tumors in animals
and efficiently transform cells in culture


About 40 ACVs have been isolated


These are called acutely transforming viruses (ACVs)
The first ACV virus, the Rous sarcoma virus (RSV), was isolated from
chicken by Peyton Rous in 1911
During the 1970s, RSV research led to the discovery of
oncogenes (genes that promote cancer)

Mutant RSV strains did not transform chicken fibroblast cells



These RSV strains contained a defective viral gene designated src
 For sarcoma, the type of cancer it causes
The src gene is also designated v–src (for viral src)
It is the first example of a viral oncogene
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22-45

The v–src gene is not important for viral replication


So researchers wondered why should the virus carry it?
Harold Varmus and Michael Bishop discovered that viral
oncogenes had a cellular origin!

A normal copy of the src gene is found in the host cell’s chromosome
It is designated c–src (for cellular src)

Once incorporated into the viral genome, c–src can now cause cancer

There are two possible explanations
 1. Viral replication leads to overexpression of the src gene


2. The v–src gene may accumulate additional mutations that
convert it into an oncogene
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22-46


RSV acquires the src gene during its life cycle
RSV is a retrovirus


It uses reverse transcriptase to make a DNA copy of its RNA genome
The DNA becomes integrated as a provirus in the host genome





The integration may occur next to a proto-oncogene
During transcription of the proviral DNA, the proto-oncogene may be
included in the RNA transcript
This RNA transcript can then recombine with an RNA retroviral
genome within the cell
This results in a retrovirus that contains an oncogene
Since the early studies on RSV, several cancer-causing
viruses have been identified

Refer to Table 22.6
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22-47
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22-48
Experiment 22A: Cellular DNA
Can Cause Transformation



In 1979, Robert Weinberg and his colleagues wanted to
determine if chromosomal DNA from malignant cells can
transform normal cells into malignant cells
Let’s first consider how malignant cells are identified
A widely used assay relies on the differential growth pattern of
normal vs. malignant cells


Normal cells grow to form a monolayer
Malignant cells pile up to form a mass of cells called a focus (Fig. 22.8)

At the microscopic level, the malignant cells also have altered shapes
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22-49
The Hypothesis

Cellular DNA isolated from malignant cells will be
taken up by normal cells and transform them into
malignant cells
Testing the Hypothesis

Refer to Figure 22.9
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22-50
Figure 22.9
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22-51
Figure 22.9
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22-52
The Data
Source of DNA
Recipient Cells
Number of
Malignant Foci
Found on 12
plates
48*
MCA16
MB66 MCA ad 36
MB66 MCA ACL6
MB66 MCA ACL13
NIH3T3
(normal fibroblasts)
NIH3T3
NIH3T3
NIH3T3
NIH3T3
Normal Cell Lines
NIH3T3
C3H10T1/2
NIH3T3
NIH3T3
<1
0
Malignant Cell Lines
MC5-5-0
5
8
0
0
*In this experiment, 2 of the plates were contaminated, so this is
48 foci on 10 plates
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22-53
Interpreting the Data
Source of DNA
Recipient Cells
Number of
Malignant Foci
Found on 12
plates
48*
MCA16
MB66 MCA ad 36
MB66 MCA ACL6
MB66 MCA ACL13
NIH3T3
(normal fibroblasts)
NIH3T3
NIH3T3
NIH3T3
NIH3T3
Normal Cell Lines
NIH3T3
C3H10T1/2
NIH3T3
NIH3T3
<1
0
Malignant Cell Lines
MC5-5-0
5
8
0
0
*In this experiment, 2 of the plates were contaminated, so this is
48 foci on 10 plates
DNA isolated from these
malignant cells could
transform normal mouse cells
It is not clear why there
was no transformation here
It could be that some
oncogenes act in a
dominant fashion, while
others act recessively
DNA isolated from normal
cells did not cause
significant transformation
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22-54
Oncogenes and Their Effects on
Cell Division

In eukaryotes, the cell cycle is regulated in part by
polypeptide hormones known as growth factors


Growth factors bind to cell surface receptors and initiate a
cascade of cellular events leading ultimately to cell division
Epidermal growth factor (EGF) is a growth hormone

Figure 22.10 shows its mechanism of action
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22-55
Binds to two EGF receptors
causing them to dimerize and
phosphorylate each other
This leads to the activation of an
intracellular signaling pathway
GTPase
Protein
kinases
EGF hormone
Protein
kinase
Transcription factors
are activated
This leads to
transcription of genes
involved in promoting
cell division
Figure 22.10
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22-56
22-57

An oncogene may promote cancer by keeping the
cell growth signaling pathway permanently “ON”

This can occur in two ways:

1. The oncogene may be overexpressed



This yields too much of the encoded protein
E.g., c-myc gene is amplified about 10-fold in a human
promyelocytic leukemia cell
2. The oncogene may produce an aberrant protein


E.g., Mutations that alter the amino acid sequence of the Ras
protein, keep the cell division signaling pathway turned on
Refer to Figure 22.11
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22-58


Mutations that convert
normal ras into an
oncongenic ras either/or
 Decrease the GTPase
activity of the Ras
protein
 Increase the rate of
exchange of bound
GDP for GTP
This results in greater
amounts of the active
Ras/GTP complex
 Signaling pathway
stays ON
Figure 22.11 Functional cycle of the Ras protein
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22-59
Proto-Oncogenes Can Be
Converted into Oncogenes

A proto-oncogene is a normal cellular gene that
can incur a mutation to become an oncogene


How this occurs is a fundamental issue in cancer biology
By studying proto-oncogenes, researchers have found
that this occurs in four main ways:





1.
2.
3.
4.
Missense mutations
Gene amplifications
Chromosomal translocations
Viral integration
Refer to Table 22.8
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22-60
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22-61

Missense mutations can convert ras genes into oncogenes

The human genome contains four different but evolutionary related ras
genes




rasH, rasN, rasK-4a, and rasK-4b
Missense mutants in these genes are associated with certain cancers
For example
Experimentally, chemical carcinogens have been shown to cause
these missense mutations and thereby lead to cancer
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22-62

Many human cancers are associated with the amplification of
particular oncogenes


Amplification of N-myc in neuroblastom
 and erbB-2 in breast carcinoma
Specific types of chromosomal translocations have been
identified in certain types of tumors

In 1960, Peter Nowell discovered that chronic myelogenous leukemia
was correlated with the presence of a shortened chromosome 22

He called this the Philadelphia chromosome after the city where it was
discovered

The cause is not a deletion;
 Rather a translocation between chromosomes 9 and 22

Refer to Figure 22.12
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22-63
A protooncogene
An oncogene
that encodes an
abnormal fusion
protein
Figure 22.12
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22-64
Tumor-Suppressor Genes and
Their Effects on Cell Division

Tumor-suppressor genes prevent the proliferation of
cancer cells


If they are inactivated by mutation, it becomes more likely
that cancer will occur
The first identification of a human tumor-suppressor
gene involved studies of retinoblastoma

A tumor of the retina of the eye
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22-65

There are two types of retinoblastoma
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1. Inherited, which occurs in the first few years of life
2. Noninherited, which occurs later in life
Alfred Knudson proposed a “two-hit” model for retinoblastoma
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Retinoblastoma requires two mutation to occur
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People with the inherited form have already received one mutation
from one of their parents
 It is not unlikely that a second mutation occurs in one of the retinal
cells at an early age, leading to disease
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People with the noninherited form, must have two mutations in the
same retinal cell to cause the disease
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
Two rare events are much less likely to occur than a single event
Therefore, the noninherited form occurs much later in life, and only rarely
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22-66


Since Knudson’s original hypothesis in 1971, molecular
studies have confirmed the “two-hit” hypothesis

The rb gene (for retinoblastoma) is on the long arm of chromosome 13
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Most individuals have two normal copies of this gene
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Persons with hereditary retinoblastoma have inherited one functionally
defective copy
 In nontumorous cells of the body, they have one normal copy and
one defective copy of rb
 In retinal tumor cells, the normal rb gene has also suffered the
second hit, rendering it defective
More recent studies have revealed how the Rb protein
prevents the proliferation of cancer cells

Refer to Figure 22.13
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22-67
Rb is phosphorylated
by cyclin-dependent
kinases when the cell
is about to divide
Transcription
factor
Figure 22.13

Genes required for cell
cycle progression
Thus, when both copies of the Rb protein are defective, the E2F protein is
always active

This leads to uncontrolled cell division
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22-68
The p53 Gene: The Master
Tumor-Suppressor Gene

The p53 gene was the second tumor-suppressor
gene discovered

About 50% of all human cancers are associated with
defects in the p53 gene

A primary role for the p53 protein is to determine if a
cell has incurred DNA damage

If so, p53 will promote three types of cellular pathways to
prevent the division of cells with damaged DNA
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22-69


p53 contains a DNA-binding
domain and a transcriptional
activation domain
It can
Induction of the p53 gene leads to the
synthesis of the p53 protein, which
functions as a transcription factor
Figure 22.14
Central role of p53 in preventing the proliferation of cancer cells
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
Apoptosis is a process that involves cell shrinkage,
chromatin condensation and DNA degradation
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It is facilitated by proteases known as capsases
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
These are sometimes referred to as the cell’s executioners
In apoptosis, the cell is broken down into small
vesicles

These are eventually phagocytosized by cells of the
immune system
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22-71
Other Types of
Tumor-Suppressor Genes

During the past three decades, researchers have
identified many tumor-suppressor genes

Some encode proteins that have direct effects on the
regulation of cell division

Others play a role in the proper maintenance of the
genome

Refer to Table 22.9
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
Some tumor-suppressor genes encode proteins that
function in the sensing of genome integrity


These proteins can detect abnormalities such as DNA
breaks and improperly segregated chromosomes
Many of these proteins are called checkpoint proteins

They check the integrity of the genome and prevent cells from
progressing past a certain point of the cell cycle if there is damage

Cyclins and cyclin-dependent kinases (Cdks) are
responsible for advancing a cell in the cell cycle

There are several checkpoints in the cell cycle of
human cells

Figure 22.15 shows three of the major checkpoints
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22-74


The M checkpoint is monitored by proteins
that can sense if a chromosome is not
correctly attached to the spindle apparatus
Both the G1 and G2
checkpoints involve
proteins that can sense
DNA damage

If so, these checkpoint
proteins can prevent the
formation of active
cyclin/Cdk complexes
Figure 22.15
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22-75

It should also be mentioned that the genes encoding
DNA repair enzymes are inactivated in some cancers

In these cancers, it is more likely for a cell to
accumulate mutations that
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Create an oncogene
Eliminate the function of a tumor-suppressor gene
Some geneticists do not consider DNA repair genes
as tumor-suppressor genes

Because the encoded proteins do not play a role in the
regulation of cell division
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22-76

The function of tumor-suppressor genes can be lost
in three main ways:
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1. A mutation in the tumor-suppressor gene itself
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2. DNA methylation
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The promoter could be wrecked
An early stop codon could be introduced in the coding sequence
The methylation of CpG islands near the promoters of tumorsuppressor genes, inhibits transcription
3. Aneuploidy

Chromosome loss may contribute to the progression of cancer if
the lost chromosome carries one or more tumor-suppressor genes
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Most Cancers Involve
Multiple Genetic Changes

Many cancers begin with a benign mutation that,
with time and more mutations leads to malignancy
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Furthermore, a malignancy can continue to accumulate
genetic changes that make it even more difficult to treat
In 1990, Eric Fearon and Bert Vogelstein proposed
a series of genetic changes that leads to colorectal
cancer


The second most common cancer in the US
Refer to Figure 22.16
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APC is a tumorsuppressor gene
Figure 22.16
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Note that the order of
mutations is not absolute
It is the total number of
genetic changes, not their
exact order, that is
important
Figure 22.16
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22-80
Inherited Forms of Cancers

As mentioned earlier, about 5% to 10% of all
cancers involve germ-line mutations
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Genetic testing exists for certain types of cancer
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People who have inherited such mutations have a
predisposition to develop cancer
Familial adenomatous polyposis
Most inherited forms of cancer involve a defect in
tumor-suppressor genes

Refer to Table 22.10
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Inherited Forms of Cancers

Some inherited forms of cancer are due to the
activation of an oncogene

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E.g., Multiple endocrine neoplasia type 2
Other inherited forms of cancer are associated with
defect in DNA repair enzymes

E.g., The genes MSH2 and MLH1 are associated with
nonpolyposis colorectal cancer
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