CANCER IS A GENETIC DISEASE

1
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
T1-1
2
A TYPICAL FAMILY TREE OF INHERITED CANCER
SYNDROME
Individuals With Related Cancer
T1-2
3
Inherited Cancer Syndrome
Sporadic Cancer
Germline mutation
Somatic mutation
Early onset
Later in life
More than one tumor
Clonal tumor
Rare
One in four people
T1-3
4
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
T1-4
5
Avian Sarcoma Virus Isolated by P. Rous in the
early 1900s
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
T1-4
6
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.
T1-6
7
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
T1-7
8
EXISTENCE OF GAIN OF FUNCTION GENETIC ALTERATIONS
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)
T1-8
9
Experiment
Prepare Total DNA from Human Bladder Cancer Cells
(EJ)
Transfection
Immortalized Mouse Fibroblasts (3T3)
Transformation Assay
Isolate Transformed clones in soft agar
Prepare DNA from these clones transfect DNA
again into
T1-9
10
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!
T1-10
11
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
T1-11
12
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
rearrangement in 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.
T1-12
13
Clonal Development of Cancer
Example Abelson murine leukemia virus causes
B-lymphoma that kills the mice in 3-6 weeks.
The virus can infect almost every cell in the
mouse, but, it only causes B-lymphoma which is
monoclonal!
T1-13
14
CANCER CELLS DIFFER FROM NORMAL CELLS BECAUSE
CANCER CELLS CONTAIN MULTIPLE GENETIC AND
EPIGENETIC ALTERATIONS
T1-14
15
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!
3. Clonality of cancer.
T1-15
16
HERITABLE ALTERATIONS IN CANCER CELLS
GAIN OF FUNCTIONS (NOT FOUND IN NORMAL CELLS)
Creation of Oncogenes
LOSS OF FUNCTIONS (FOUND IN NORMAL CELLS)
Destruction of Tumor Suppressor Genes
T1-16
17
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 requires the
uncoupling of these processes, hence, it
requires a multitude of alterations.
T1-17
18
Normal Proliferation is Coupled to Multiple
Choices
Proliferation
Senescence
Stem cell
Apoptosis
Quiescence
Differentiation
Long-term survival
death
T1-18
19
Cancer Proliferation is Uncoupled from the
Normal Choices
Proliferation
Senescence
Cancer cell
Apoptosis
Quiescence
Differentiation
T1-19
20
Cancer Proliferation is Uncoupled from the
Normal Choices
More Cyclins
Loss of p16
Senescence
Proliferation
Loss of Arf
Cancer cell
Reactivation of telomerase
Gain of Ras Gain of growth factors
Gain of Bcl2
Loss of p53
Apoptosis
Gain of Myc
Quiescence
Loss of RB
Differentiation
T1-20
21
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 THERAPY BASED ON
CANCER GENES
T1-21