Transcript Brooker Chapter 22 - Volunteer State Community College

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Genetics: Analysis and Principles
Robert J. Brooker
CHAPTER 22
MEDICAL GENETICS
CANCER
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AND
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; clonal
2. At the cellular and genetic levels, cancer is
usually a multistep process



It begins with a precancerous genetic change (i.e., a
benign growth)
Following additional genetic changes, it progresses to
cancerous cell growth
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
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Figure 18-3
Copyright © 2006 Pearson Prentice Hall, Inc.
The growth and metastasis of a
malignant breast tumor
Lymph
vessel
Tumor
Glandular
tissue
1 A tumor grows from a
single cancer cell.
2 Cancer cells invade
neighboring tissue.
Blood
vessel
Cancer cell
3 Cancer cells spread
through lymph and
blood vessels to
other parts of the body.
Metastatic
Tumor
4 A small percentage of
cancer cells may survive
and establish a new tumor
in another part of the body.

~ 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; carcinogens

These alter the structure and expression of genes
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22-43
Certain Viruses Can Cause Cancer

The process of converting a normal cell into a
malignant cell is termed transformation
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22-44

A few viruses can rapidly induce tumors in animals
and efficiently transform cells in culture; 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)
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22-45

The v–src gene is not important for viral replication

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 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
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


During transcription of the proviral DNA, the protooncogene 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
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

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
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22-50
Figure 22.9
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22-51
“transfection”
Figure 22.9
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22-52
Density-dependent inhibition of cell division
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
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
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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”

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
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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
Inactivated by phosphorylation
C-term regulatory region deleted; cannot be inactivated
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 or deletion mutations
Gene amplifications
Chromosomal translocations
Viral integration
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22-60
Also happens because of
nearby viral integration
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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

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
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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
Burkitt’s Lymphoma
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


1. Inherited, which occurs in the first few years of life
2. Noninherited, which occurs later in life

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

People with the noninherited form, must have two mutations
in the same retinal cell to cause the disease


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

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
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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
Rb is also a target of a viral
oncogene in cervical cancers
Viral oncoproteins counter the action of cellular
tumour suppressors
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
22-70

Apoptosis is a process that involves cell shrinkage,
chromatin condensation and DNA degradation

It is facilitated by proteases known as capsases


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


Normal white
blood cell
Apoptotic cell
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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22-73

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
Levels of cyklins vary through the
cell cycle
Cyclin B controls progression through
mitosis by stimulating CDK1 activity

Genes encoding DNA repair enzymes may be
inactivated in some cancers

In these cancers, it is more likely for a cell to
accumulate mutations that


Create an oncogene
Eliminate the function of a tumor-suppressor gene
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22-76

The function of tumor-suppressor genes can be lost
in three main ways:

1. A mutation in the tumor-suppressor gene itself



2. DNA methylation


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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22-77
Most Cancers Involve
Multiple Genetic Changes

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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22-78
APC is a tumorsuppressor gene
Figure 22.16
22-79
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


Genetic testing exists for certain types of cancer


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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22-81
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22-82
Inherited Forms of Cancers

Some inherited forms of cancer are due to the
activation of an oncogene


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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22-83
hereditary nonpolyposis colorectal cancer
(HNPCC): mutations in genes for DNA
repair
Figure 18-6
Copyright © 2006 Pearson Prentice Hall, Inc.
Table 18-3
Copyright © 2006 Pearson Prentice Hall, Inc.