1. 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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2. 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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3. ~ 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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4. 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
G1 checkpoint
(DNA damage)
G2 checkpoint
(Cell size)
M checkpoint
(Spindle assembly)

5. 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

6. 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

7. 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

8. ~ 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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9. 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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10. 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.

11. 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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12. 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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13. 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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14. 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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15. The p53 Gene: The Master Tumor-Suppressor Gene
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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16. 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

17. 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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18. 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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19. retinoblastoma

20. Most individuals have two normal copies of this gene related to retinoblastoma
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
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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21. ( Development of cancer at the cellular level (Inherited mutation)
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Normal cell
Cancer cell
BRCA-1
BRCA-1
BRCA-1
BRCA-1
( Development of cancer at the cellular level
(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
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