Transcript Human Genetics

Human Genetics
Concepts and Applications
Tenth Edition
RICKI LEWIS
18
Genetics
of Cancer
PowerPoint® Lecture Outlines
Prepared by Johnny El-Rady, University of South Florida
Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display
Introduction
Cancer has been part of human existence
for eons
By 300 B.C., Hippocrates coined the term
“cancer” to describe the crablike shape of
a tumor invading normal tissue
Cancer has or will affect one in three of us
Diagnosis and treatment are becoming
increasingly individualized
2
Introduction
Cancer is genetic, but is not usually inherited
Carcinogens are substances that cause
cancer
- Most are mutagens (damage DNA)
Cancer is a group of diseases caused by loss
of cell cycle control
- If a cell escapes normal control over its
division rate, it forms a growth called a
tumor
3
Figure 18.1
4
Introduction
A tumor is benign if it does not spread or
“invade” surrounding tissue
A tumor is cancerous or malignant if it
infiltrates nearby tissues
Metastasis
- The tumor spreads to other parts of the
body via the blood or lymph vessels
5
Cancer-Causing Genes
Oncogenes
- More than 100
- Cause cancer if inappropriately activated
Tumor suppressor genes
- More than 30
- Deletion or inactivation causes cancer
- Cell cycle control/checkpoints
In addition, changes in gene expression
accompany cancer
6
Cell Cycle Control
Timing, rate, and number of cell divisions
depend on:
- Protein growth factors
- Signaling molecules from outside the cell
- Transcription factors within
Checkpoints control the cell cycle
- Ensure that mitotic events occur in the
correct sequence
7
Cell Cycle Control
Figure 18.2
8
Loss of Cell Cycle Control
Many types of cancer result from faulty
check points
Cancer sends a cell down a pathway of
unrestricted cell division
Cancer cells either lose specializations or
never specialize
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Figure 18.3
10
Telomeres and Telomerase
Loss of control of telomere length may
also contribute to cancer
Telomerase is the enzyme (complex of
RNA and protein) that adds telomere
sequences to the ends of chromosomes
Normal, specialized cells have telomerase
turned off, limits cell division
Cancer cells have to express telomerase
to be able to divide indefinitely
11
Inherited vs. Sporadic Cancer
Somatic mutations
- Occur sporadically in nonsex cells
- Result from a single dominant mutation or two
recessive mutations in the same gene
- Cancer susceptibility not passed on to offspring
Germline mutations
- Cancer susceptibility passed on to offspring
- Usually requires second somatic mutation
- Rarer but strike earlier than sporadic cancers
12
Inherited vs. Sporadic Cancer
Figure 18.4
13
Origin of Cancer
Cancer begins at the genetic and cellular
levels
If not halted, cancer spreads through tissues
to take over organs and organ systems
The origin and spread of cancer are
summarized next
14
Figure 18.5
15
Characteristics of Cancer Cells
Divide continually (given space and
nutrients), and quicker than normal cells
Contain heritable mutations
Transplantable
Dedifferentiated: lose their specialized
identity
Have a different appearance
Cell surface has different types and/or
number of antigen
16
Characteristics of Cancer Cells
Lack contact inhibition
Induce angiogenesis: formation of local
blood vessels
Invasive: squeeze into any space available
Metastasize: move to new location in body
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Figure 18.6
18
Angiogenesis Nurtures a Tumor
Figure 18.7
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Table 18.2
21
Origins of Cancer Cells
Cancer can begin at the cellular level in at
least four ways:
- Activation of stem cells that produce
cancer cells
- Dedifferentiation
- Increase in proportion of a tissue that
consists of stem cells or progenitor cells
- Faulty tissue repair
22
Figure 18.8
23
Cancer By Loss of Specialization
Specialized cells lose some of their
distinguishing features as mutations
occur when they divide
Result is dedifferentiation
A biochemical “reversine” may stimulate
differentiated cells to divide and produce
progenitor cells in mice
24
Dedifferentiation Reverses Specialization
Figure 18.9
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Cancers from Shifting Balance
of Cell Types in a Tissue
Figure 18.10
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Uncontrolled Tissue Repair
May Cause Cancer
Figure 18.11
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Oncogenes
Proto-oncogenes are normal versions of
genes that promote cell division
Expression at the wrong time or in the
wrong cell type leads to cell division and
cancer
Proto-oncogenes are called oncogenes in
their mutated form
One copy of an oncogenic mutation is
sufficient to promote cell division
28
Oncogenes:
Overexpression of a Normal Function
Viruses integrated next to a proto-oncogene
can cause transcription when the virus is
transcribed
Moving a proto-oncogene next to a highly
transcribed gene can lead to
overexpression of the proto-oncogene
Example: Burkitt lymphoma
- A translocation places a proto-oncogene
next to an antibody gene
29
Oncogenes:
Overexpression of a Normal Function
Chromosome 8
Chromosome
14
Figure 18.12
30
Fusion Proteins
Oncogenes are activated when a protooncogene moves next to another gene
The gene pair is transcribed together
The double gene product is a fusion protein
- It activates or lifts control of cell division
31
Acute Promyelocytic Leukemia
Translocation between chromosomes 15
and 17
Combination of retinoic acid cell surface
receptor and an oncogene, myl
Fusion protein functions as a transcription
factor
- When overexpressed causes cancer
Some patients respond to retinoid drugs
32
Chronic Myelogenous Leukemia (CML)
Most patients have a translocated
Philadelphia chromosome (tip of 9 on 22)
Abl (chromosome 9) and bcr (chromosome
22) genes produce a fusion protein
BCR-ABL oncoprotein is a tyrosine kinase
that excessively stimulates cell division
Understanding cellular changes allowed
development of new drug, Gleevec, for
treatment
33
Reading 18.1, Figure 2
34
Her-2/neu
Product of an oncogene
Excessive levels in approximately 25% of
breast cancer patients
Too many receptors
Too many signals to divide
Monoclonal antibody drug, Herceptin,
binds to receptors, blocking signal to
divide
35
Tumor Suppressor Genes
Cancer can be caused by loss of genes
that inhibit cell division
Tumor suppressor genes normally stop a
cell from dividing
Mutations of both copies of a tumor
suppressor gene is usually required to
allow cell division
Genes can also be lost by deletion or
silenced by promoter hypermethylation
36
Retinoblastoma (RB)
A rare childhood cancer
The RB gene is on chromosome 13
The RB protein binds transcription factors
so that they cannot activate genes that
carry out mitosis
- Normally halts the cell cycle at G1
Study of RB was the origin of the “two-hit”
hypothesis of cancer causation
37
Two-Hit Hypothesis
Two mutations or deletions are required
- One in each copy of the RB gene
For sporadic cases (non-inherited)
- Retinoblastoma is a result of two somatic
mutations
For familial cases (inherited)
- Individuals harbor one germline mutant allele
for the RB gene in each of their cells
- This is followed by a somatic mutation in the
normal allele
38
p53
The p53 gene is the “guardian of the genome”
Determines if a cell has repaired DNA damage
If damage cannot be repaired, p53 can induce
apoptosis
More than 50% of human cancers involve an
abnormal p53 gene
Rare inherited mutations in the p53 gene cause
a disease called Li-Fraumeni syndrome
- Family members have many different types
of cancer at early ages
39
Figure 18.13
40
Breast Cancer
Two main forms
- Familial form: A germline mutation is
inherited and then a somatic mutation
occurs in a breast cell
- Sporadic form: Two somatic mutations
affect the same cell
Mutations in many genes can cause cancer
41
BRCA
The two major breast-cancer susceptibility
genes are BRCA1 and BRCA2
- Encode proteins that join two others to
form a complex that allows repair of
double-stranded DNA breaks
Mutations in these genes have different
incidences in different populations
Inheriting BRCA mutations increases the
risk of other types of cancer
42
Other Genes
Genes whose protein products affect those
of BRCA1, BRCA2, and p53 can cause
breast cancer
Example: The ATM gene product adds a
phosphate to the CHEK2 gene product,
which then adds a phosphate to the
BRCA1 protein
- Mutations in ATM and CHEK2 can
cause breast cancer
43
MicroRNAs Revisited
MicroRNAs normally control the expression
of proto-oncogenes and tumor
suppressor genes
- Thus, when they are mutated or
differentially expressed, cancer can result
Patterns of microRNA expression change
as a cancer progresses
- This is being used to develop new,
more sensitive ways to diagnose and
treat cancer
44
Types of Genes
Gatekeeper genes
- Directly control mitosis and apoptosis
Caretaker genes
- Control mutation rates and may have
an overall effect, when mutant, in
destabilizing the genome
Most cancers are the culmination of a
series of mutations in several genes
45
Familial Adenomatous Polyposis
(FAP)
5% of colon cancer cases are inherited
1 in 5000 in U.S. has FAP
Causes multiple polyps at an early age
Several mutations contribute
- APC genes mutate
- Activation of oncogenes (E.g. K-Ras)
- Mutations in TGF, p53, and other genes
- PRL-3 triggers metastasis
- Caretaker genes cause genomic instability
46
Figure 18.14
47
The Cancer Genome
Several large-scale projects are analyzing
genomes of cancer cells
- These allow construction of descriptive
“atlases” containing different types of
information
Many mutations accompany cancer, but
they interact in only a few pathways
- Once a pathway is implicated, scientists
can look for or develop drugs to target it
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Table 18.3
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Environmental Causes of
Cancer
Environmental factors contribute to cancer
by mutating or altering the expression of
genes that control the cell cycle,
apoptosis, and DNA repair
Inheriting a susceptibility gene places a
person farther along the road to cancer
- However, cancer can happen in somatic
cells in anyone
50
Environmental Causes of
Cancer
Individuals can lower the chance of
developing cancer by:
- Avoiding high-risk environmental factors,
such as smoking and excess sun
exposure
- Taking “chemopreventative” nutrients
such as folic acid and vitamin D
51
Cruciferous
Vegetables
Can Lower
Cancer Risk
Figure 18.15
52
Methods to Study CancerEnvironment Links
Population Study: Compares incidence of a type
of cancer among different groups of people
Case Control: Identify differences between
patients with a type of cancer and healthy
individuals matched for multiple characteristics
Prospective Studies: Two or more groups of
individuals follow a specific regimen ( e.g., diet
or activity plan) and are checked regularly for
cancer
53
Figure 18.16
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Cancer Diagnosis and Treatment
Most often, discovery of cancer follows a
screening test
Oldest treatment is surgery, which removes
the tumor
Radiation and chemotherapy non-selectively
destroy rapidly dividing cells
Other drugs help patients tolerate the side
effects
55
Cancer Diagnosis and Treatment
New types of cancer drugs:
- Stimulate cells to regain specialized
characteristics
- Inhibit telomerase
- Induce apoptosis
- Inhibit angiogenesis
Genomics information is increasingly used
- Enables physicians to better match
patient to treatment
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Table 18.6
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