1. Medical Genetics and Cancer

2. INTRODUCTION Approximately 12,000 genetic diseases afflict people
This is probably an underestimate
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
May involve multiple genes
E.g., Diabetes, asthma, mental illness
Unraveling the complexities of these diseases will be a challenge for some time to come
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3. 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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4. 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
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5. A family pedigree of Tay-Sachs disease

6. A family pedigree of Huntington disease

7. The inheritance pattern of hemophilia A in the royal families of Europe

8. Genetic screening refers to population-wide genetic testing
Genetic testing refers to the use of tests to discover if an individual carries a genetic abnormality
Genetic screening refers to population-wide genetic testing
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9. Single gene mutations can also be examined at the level of the gene
In many cases, single-gene mutation that affect proteins, can be examined at the protein level
Biochemical assays may be available for enzymes
Single gene mutations can also be examined at the level of the gene
- Sequencing previously identified the mutant gene using molecular techniques
A 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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10. 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
Rates of such defects increase with the age of the mother
Widespread screening for phenylketonuria
Genetic testing has also been conducted on specific population in which a genetic disease is prevalent
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11. Another issue is privacy
Genetic testing and screening are medical practices with many social and ethical dimensions
Do people want to know if they have a mutant gene
Especially unclear if there is no known treatment
May do more harm than good
Another issue is privacy
Could employers or insurance companies discriminate against someone with a positive genetic test
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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13. 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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14. Cancer characteristics
1. Most cancers originate in a single cell
In this regard, a cancerous growth can be considered to be 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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15. ~ 1 million Americans are diagnosed with cancer each year
About 500,000 will die from the disease
5-10% of cancers are due to inherited predisposition
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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16. 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

17. Control of Cell Cycle
Cell cycle checkpoints are control mechanisms that ensure the fidelity of cell division in eukaryotic cells. These checkpoints verify whether the processes at each phase of the cell cycle have been accurately completed before progression to the next phase.
function of many checkpoints is to assess DNA damage, which is detected by sensor mechanisms – function of Checkpoint proteins

18. Proteins with a role in Cancer
Checkpoint proteins prevent division of cells that may have incurred DNA damage
Provides a mechanism to stop accumulation of genetic abnormalities that could produce cancer
A second class of proteins involved with genome maintenance consists of DNA repair enzymes

19. Progression of cellular growth leading to cancer

20. 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
Most cancer-causing viruses are not very potent at inducing cancer
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21. Two major classes of cancer causing genes
Oncogenes - Proto-oncogenes are genes that normally help cells grow. When a proto-oncogene mutates (changes) or there are too many copies of it, it becomes a "bad" gene that can become permanently turned on or activated when it is not supposed to be. When this happens, the cell grows out of control, which can lead to cancer. This bad gene is called an oncogene.
Tumor Suppressor genes - Tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (a process known as apoptosis or programmed cell death). When tumor suppressor genes don't work properly, cells can grow out of control, which can lead to cancer.

22. Expression becomes abnormally active
proto-oncogenes are normal cellular genes that can be mutated into an oncogene.
Expression becomes abnormally active
This can occur in three ways:
1. The oncogene may be overexpressed
This yields too much of the encoded protein
2. The oncogene may produce an aberrant protein
Mutations that alter the amino acid sequence of a cell cycle protein, keep the cell division signaling pathway turned on
3. The oncogene may be expressed in a cell type where it is not normally expressed
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23. 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 mutations
2. Gene amplifications
3. Chromosomal translocations
4. Viral integration
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24. Missense mutations can convert proto-oncogenes into oncogenes
Experimentally, chemical carcinogens have been shown to cause these missense mutations and thereby lead to cancer
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25. 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
chronic myelogenous leukemia was correlated with the presence of a shortened chromosome 22
This was 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
This puts the proto-oncogene abl under the control of the bcr promoter, which is active in white blood cells, leading to leukemia
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26. An oncogene that encodes an abnormal fusion protein
A proto-oncogene
An oncogene that encodes an abnormal fusion protein
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27. 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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28. retinoblastoma

29. There are two types of retinoblastoma
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
Retinoblastoma requires two mutation to occur
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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30. 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
Most individuals have two normal copies of this gene
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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31. 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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32. Central role of p53 in preventing the proliferation of cancer cells
In multi-cellular organisms, individual cells which have undergone irreparable DNA damage will go through programmed cell death
Central role of p53 in preventing the proliferation of cancer cells

33. Roles 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
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34. Some tumor-suppressor genes encode proteins that function in the sensing of genome integrity
genome maintenance refers to the mechanisms that prevent mutations or prevent mutant cells from surviving or dividing
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
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35. 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 inactivated
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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36. Genetic Changes leading to Cancer
Some genes affect growth directly, others may enable metastasis which allows expansion to new locations, giving the cells a growth advantage
Estimated that 300 different genes may play a role in development of human cancer
over 1% of our genes
Chromosomal abnormalities are often associated with cancer
Missing chromosomes may have carried tumor suppressor
Duplicated chromosomes may overexpress proto-oncogenes
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37. Karyotype from a cancer cell (right) show fusions of chromosomes, duplications and
deletions
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38. 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
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39. Inherited Forms of Cancers
Predisposition for developing cancer is often the result of being heterozygous for one of these genes
Cancer results from loss of the normal copy
This is known as loss of heterozygosity (LOH)
Tends to be inherited in a dominant fashion
Can result from point mutation in normal allele
Can also occur if chromosome carrying good copy is lost
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40. Heterozygous for BRCA-1 mutation, affected
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Homozygous normal
Heterozygous for BRCA-1 mutation, affected ,
Heterozygous for BRCA-1 mutation, unaffected
Normal cell
Cancer cell
BRCA-1
BRCA-1
BRCA-1
BRCA-1
(Inherited
mutation)
(Occurs
in a
somatic
cell)
(Inherited
mutation)
Heterozygote – cell
has one functional
copy of BRCA-1
Loss of heterozygosity –
cell has zero functional
copies of BRCA-1
(a) Pedigree for familial breast cancer
(b) Development of cancer at the cellular level
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