CANCER IS A GENETIC DISEASE

SUPPORTING EVIDENCE:

1. Hereditary cancer

2. Cancer-causing virus

3. Alterations of cellular genes in cancer

4. Clonal development of cancer

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A TYPICAL FAMILY TREE OF INHERITED CANCER SYNDROME

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IndividualsWith Related Cancer

Inherited Cancer Syndrome:

Germline mutation

Early onset

More than one tumor

Rare

Sporadic Cancer:

Somatic mutation

Later in life

Clonal tumor

One in four people

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CANCER IS A GENETIC DISEASE

SUPPORTING EVIDENCE:

1. Hereditary cancer

2. Cancer-causing virus

3. Alterations of cellular genes in cancer

4. Clonal development of cancer

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Avian Sarcoma Virus Isolated by P. Rous in the early 1900’s

1. A retrovirus

2. Can be transmitted from chick to chick

3. Causes sarcoma, cancer of the connective tissue (fibroblasts)

4. Carries an “oncogene”, called src

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Viral Oncogene

Originates in the virus. Viral oncogene product interacts with host proteins to cause trouble.Examples: T-antigen, E1A.

Originates in the host. Viral transduction of altered host genes to cause trouble. Examples: v-Src, v-Ras, v-Myc, v-Abl.

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CANCER IS A GENETIC DISEASE

SUPPORTING EVIDENCE:

1. Hereditary cancer

2. Cancer-causing virus

3. Alterations of cellular genes in cancer

4. Clonal development of cancer

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EXISTENCE OF GAIN OF FUNCTION GENETICALTERATIONS IN SPORADIC CANCER CELLS

Method: Forcing DNA into Immortalized Mouse Cells (Transfection)

Biological Assay: Transformation of immortalized mouse cells into tumorigenic mouse cells: • growth in soft agar • tumor formation in immune-deficient mice (nude mice)

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Experiment

Prepare Total DNA from Human Bladder Cancer Cells (EJ)

Transfection

Immortalized Mouse Fibroblasts (3T3)

Transformation Assay

Prepare DNA from these clones& transfect DNA again into

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Isolate Transformed clones in soft agar

Results

• DNA from human bladder cancer cells can convert immortalized mouse cells into tumorigenic cells.

• Repeated transfections allowed scientists to reduce the amount of human DNA in the tumorigenic mouse cells (purification of transforming DNA).

• Human DNA contains signature repetitive sequences that are not in the mouse gnome.

• Therefore, scientists were able to “isolate (clone)” the human DNA that caused tumorigenic conversion. Nucleotide sequencing identified this transforming gene to be a mutated Ras*!

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CANCER IS A GENETIC DISEASE

SUPPORTING EVIDENCE:

1. Hereditary cancer

2. Cancer-causing virus

3. Alterations of cellular genes in cancer

4. Clonal development of cancer

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Clonal Development of Cancer

Cancer of the B-lymphocytes (various forms of Leukemia or Lymphoma)can be shown to be monoclonal or oligoclonal by the analysis of immunoglobulin (Ig) genes, which undergo random rearrangementin B cells. Hence, the cancer cells are the Descendants of a few transformed B cells. Mixture of B cells: Ig genes in many different configurations due to random rearrangement

A monoclonal population of B cells: Ig gene in one configuration.

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Example:Abelson murine leukemia virus causes B-lymphoma thatkills the mice in 3-6 weeks.

The virus can infect almost every cell in the mouse, but, it only causes B-lymphomawhich is monoclonal!

Clonal Development of Cancer

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CANCER CELLS DIFFER FROM

NORMAL CELLS BECAUSE

CANCER CELLS CONTAINMULTIPLE

GENETIC AND EPIGENETICALTERATIONS

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Cancer Development is Driven by Multiple Defects

Evidence

1. Cancer rate increases with age.

2. A single mutation is not sufficient to cause cancer.

Ras* does not transform normal cells, it only transforms“immortalized” mouse cells, which grow forever!

Ras* actually causes primary cells to stop growing!

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HERITABLE ALTERATIONS IN CANCER CELLS

•GAIN OF FUNCTIONS (NOT FOUND IN NORMAL CELLS)

•LOSS OF FUNCTIONS (FOUND IN NORMAL CELLS)

Creation of Oncogenes

Destruction of Tumor Suppressor Genes

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WHY MULTIPLE ALTERATIONS?

Cell proliferation is purposeful,and can respond to stress. Normal proliferation is coupled to Differentiation, Senescence, and Death by Suicide (Apoptosis).

Deregulation of cell proliferation requiresthe uncoupling of these processes, hence, it requires a multitude of alterations.

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Normal Proliferation is Coupled to Multiple Choices

Stem cell

Proliferation

Quiescence

Differentiation

deathLong-term

survival

Senescence

Apoptosis

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Cancer Proliferation is Uncoupled from the Normal Choices

Cancercell

Proliferation

Quiescence

Differentiation

Senescence

Apoptosis

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Cancer Proliferation is Uncoupled from the Normal Choices

Cancercell

Proliferation

Quiescence

Differentiation

Senescence

Apoptosis

Reactivation of telomerase

Loss of p53

Gain of Bcl2

Gain of MycLoss of RB

Loss of Arf

More Cyclins

Gain of RasGain of growth factors

Loss of p16

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TOPICS

•DISCOVERY OF CANCER GENES

•HOW CANCER GENES CONTRIBUTE TO CANCER CELL GROWTH

•HOW CANCER GENES CONTRIBUTE TO CANCER GENETIC INSTABILITY

•RATIONAL DESIGN OF CANCER THERAPYBASED ON CANCER GENES

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