1. PowerPoint Presentation Materials to accompany
Genetics: Analysis and Principles
Robert J. Brooker
CHAPTER 22
MEDICAL GENETICS AND CANCER
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2. 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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3. Figure 18-2 The incidence of most cancers rises exponentially with age
Figure 18-2 The incidence of most cancers rises exponentially with age. This graph shows that the logarithmic plot of the incidence rate has a linear relationship with the logarithmic plot of the patient’s age.

4. 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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5. Figure 22.7 Progression of cellular growth leading to cancer
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6. Figure 18-3 Copyright © 2006 Pearson Prentice Hall, Inc.
Figure 18-3 Stages in the development of cervical cancer. (a) to (d) Steps in progression from normal cervical epithelium to a malignant carcinoma. (e) to (g) Light microscope photos of cervical biopsy samples. Note the invasive cells in (g) that have crossed the basal lamina (light area in center) and entered connective tissue below.
Figure Copyright © 2006 Pearson Prentice Hall, Inc.

7. The growth and metastasis of a malignant breast tumor
A tumor grows from a single cancer cell.
Cancer cells invade neighboring tissue.
Cancer cells spread through lymph and blood vessels to
other parts of the body.
A small percentage of cancer cells may survive and establish a new tumor in another part of the body. 2 4 3 1
Tumor
Glandular
tissue
Cancer cell
Blood vessel
Lymph vessel
Metastatic Tumor

8. ~ 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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9. Certain Viruses Can Cause Cancer
The process of converting a normal cell into a malignant cell is termed transformation
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10. 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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11. 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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12. 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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13. 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
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14. 22-48
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15. Table 18-4 Representative Viral Oncogenes

16. 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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17. 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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18. Figure 22.9
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19. 22-52 Figure 22.9 “transfection”
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20. Density-dependent inhibition of cell division

21. Interpreting the Data 22-54 Source of DNA Recipient Cells
Number of Malignant Foci Found on 12 plates
Malignant Cell Lines
MC5-5-0
MCA16
MB66 MCA ad 36
MB66 MCA ACL6
MB66 MCA ACL13
Normal Cell Lines
NIH3T3
C3H10T1/2
(normal fibroblasts)
48* 5 8
<1
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
*In this experiment, 2 of the plates were contaminated, so this is 48 foci on 10 plates
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22. 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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23. Binds to two EGF receptors causing them to dimerize and phosphorylate each other
GTPase
This leads to the activation of an intracellular signaling pathway
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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24. 22-57

26. 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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27. 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 Functional cycle of the Ras protein
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29. Inactivated by phosphorylation
C-term regulatory region deleted; cannot be inactivated

30. 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. Missense or deletion mutations
2. Gene amplifications
3. Chromosomal translocations
4. Viral integration
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31. Also happens because of nearby viral integration

32. 22-61
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33. 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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35. 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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36. An oncogene that encodes an abnormal fusion protein
A proto-oncogene
An oncogene that encodes an abnormal fusion protein
Figure 22.12
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37. Burkitt’s Lymphoma

38. 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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40. 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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42. 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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43. Genes required for cell cycle progression
Rb is phosphorylated by cyclin-dependent kinases when the cell is about to divide
Transcription factor
Genes required for cell cycle progression
Figure 22.13
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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44. Rb is also a target of a viral oncogene in cervical cancers

45. Viral oncoproteins counter the action of cellular tumour suppressors

46. 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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47. 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 Central role of p53 in preventing the proliferation of cancer cells
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48. It is facilitated by proteases known as capsases
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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49. Normal white blood cell
Figure 18-10a (a) A normal white blood cell (bottom) and a white blood cell undergoing apoptosis (top). Apoptotic bodies appear as grape-like clusters on the cell surface. (b) The relative concentrations of the Bcl2 and BAX proteins regulate apoptosis. A normal cell contains a balance of Bcl2 and BAX, which form inactive heterodimers. A relative excess of Bcl2 results in Bcl2 homodimers, which prevent apoptosis. Cancer cells with Bcl2 overexpression are resistant to chemotherapies and radiation therapies. A relative excess of BAX results in BAX homodimers, which induce apoptosis. In normal cells, activated p53 protein induces transcription of BAX and inhibits transcription of Bcl2, leading to cell death. In many cancer cells, p53 is defective, preventing the apoptotic pathway from removing the cancer cells.
Apoptotic cell

50. 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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51. 22-73

52. Figure 18-7 Checkpoints and proliferation decision points monitor the progress of the cell through the cell cycle.

53. There are several checkpoints in the cell cycle of human cells
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 shows three of the major checkpoints
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54. 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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55. Levels of cyklins vary through the cell cycle
Figure 18-8 Relative expression times and amounts of cyclins during the cell cycle. Cyclin D1 accumulates early in G1 and is expressed at a constant level through most of the cycle. Cyclin E accumulates in G1, reaches a peak, and declines by mid S phase. Cyclin D2 begins accumulating in the last half of G1, reaches a peak just after the beginning of S, and then declines by early G2. Cyclin A appears in late G1, accumulates through S phase, peaks at the G2/M transition, and is rapidly degraded. Cyclin B peaks at the G2/M transition and declines rapidly in M phase.

56. Cyclin B controls progression through mitosis by stimulating CDK1 activity
Figure 18-9 Transition from G2 to M phase is controlled by CDK1 and cyclin B. These molecules interact to form a complex that adds phosphate groups to cellular components. These in turn bring about the structural and biochemical changes necessary for mitosis (M phase).

58. 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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59. The function of tumor-suppressor genes can be lost in three main ways:
1. A mutation in the tumor-suppressor gene itself
The promoter could be wrecked
An early stop codon could be introduced in the coding sequence
2. DNA methylation
The methylation of CpG islands near the promoters of tumor-suppressor 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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60. 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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61. APC is a tumor-suppressor gene
Figure 22.16
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62. 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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63. Inherited Forms of Cancers
As mentioned earlier, about 5% to 10% of all cancers involve germ-line mutations
People who have inherited such mutations have a predisposition to develop cancer
Genetic testing exists for certain types of 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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64. 22-82
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65. 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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66. Figure 18-6 Copyright © 2006 Pearson Prentice Hall, Inc.
hereditary nonpolyposis colorectal cancer (HNPCC): mutations in genes for DNA repair
Figure 18-6 Pedigree of a family with HNPCC. Families with HNPCC are defined as those in which at least three relatives in two generations have been diagnosed with colon cancer, with one relative diagnosed at less than 50 years of age. Colon cancer: C; stomach cancer: S; endometrial cancer: E; pancreatic cancer: P; bladder/urinary cancer: B. Blue symbols indicate family members with colon cancer; diagonal stripes mean that diagnosis is uncertain; orange symbols indicate other tumors. Symbols with slashes indicate deceased individuals. Reprinted with permission from Aaltonen et.al. Clues to the pathogenesis of familial colorectal cancer. Science 260: , Figure 1. Copyright 1993 AAAS.
Figure Copyright © 2006 Pearson Prentice Hall, Inc.

67. Table 18-3 Copyright © 2006 Pearson Prentice Hall, Inc.
Table Inherited Predispositions to Cancer
Table Copyright © 2006 Pearson Prentice Hall, Inc.