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Medical Genetics
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遗传与肿瘤发生
Cancer Genetics
Medical Genetics
The ancient Greeks believed that
cancer was caused by too much body
fluid they called "black bile."
Medical Genetics
Doctors in the seventeenth and
eighteenth centuries suggested that
parasites caused cancer. Today,
doctors understand more about the
link between cancer and genetics.
Medical Genetics
Viruses, ultraviolet (UV) radiation, and
chemicals can all damage genes in the
human body. If particular genes are
affected, a person can develop cancer.
Understanding how genes cause cancer,
though, first requires a basic
understanding of several genetic terms
and concepts.
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1. General
Cancer is a very common
disease, affecting about 1 in 3
individuals, and about half the
people that contract cancer will die
as a direct result of their disease.
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Tumors are hereditary
Hereditary retinoblastoma is an
autosomal dominant trait in which
susceptibility to retinoblastoma is
inherited. This is an unusual "dominant"
trait in that a mutation in one RB gene is
not sufficient to cause symptoms, but
mutations in the second allele often arise
during development.
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Medical Genetics
The mutations occur after birth
and result in tumor formation.
Tumors usually develop in only one
eye and patients are not at high risk
for other cancers. Both alleles need
to be mutated in a single cell, and
that is why this form typically occurs
only in one eye.
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Medical Genetics
Chromosome and tumors
Detailed studies of the Philadelphia
chromosome show that most of chromosome 22
has been translocated onto the long arm of
chromosome 9. In addition, the small distal
portion of the short arm of chromosome 9 is
translocated to chromosome 22. This
translocation, which is found only in tumor cells,
indicates that a patient has chronic myelogenous
leukemia (CML). In CML, the cells that produce
blood cells for the body (the hematopoietic cells)
grow uncontrollably, leading to cancer.
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Medical Genetics
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In one of the translocated
chromosomes, part of a gene called
abl is moved from its normal location
on chromosome 9 to a new location
on chromosome 22. This breakage
and reattachment leads to an altered
abl gene. The protein produced from
the mutant abl gene functions
improperly, leading to CML.
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2. oncogene
Oncogenes are mutated forms of
genes that cause normal cells to
grow out of control and become
cancer cells. They are mutations of
certain normal genes of the cell
called proto-oncogenes.
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Proto-oncogenes are the genes that
normally control how often a cell divides
and the degree to which it differentiates
(or specializes). When a proto-oncogene
mutates (changes) into an oncogene, it
becomes permanently "turned on" or
activated when it is not supposed to be.
When this occurs, the cell divides too
quickly, which can lead to cancer.
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The pathway for normal cell growth
starts with growth factor, which locks onto
a growth factor receptor. The signal from
the receptor is sent through a signal
transducer. A transcription factor is
produced, which causes the cell to begin
dividing. If any abnormality is detected,
the cell is made to commit suicide by a
programmed cell death regulator.
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myc. In lung cancer, leukemia,
lymphoma, and a number of other
cancer types, myc is often overly
activated and stimulates cell division.
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abl and ras. Abl is activated in chronic
myelocytic leukemia. Abnormalities
of ras are found in many cancers.
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This leads to an overgrowth of
abnormal cells, which can then
become cancerous. The most well
described one is called bcl-2. It is
often activated in lymphoma cells.
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3. Tumor Suppressor Genes
Tumor suppressor genes are
normal genes that slow down cell
division, repair DNA mistakes, and
tell cells when to die (a process
known as apoptosis or programmed
cell death).
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When tumor suppressor genes do
work properly, cells can grow out of
control, which can lead to cancer.
About 30 tumor suppressor genes
have been identified, including p53,
BRCA1, BRCA2, APC, and RB1. Some
of these will be described in more
detail later on.
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Types of Tumor Suppressor Genes
Genes that control cell division
Genes that repair DNA
Cell "suicide" genes
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Genes that control cell division
Some tumor suppressor genes
help control cell growth and
reproduction. The RB1
(retinoblastoma) gene is an example
of such a gene. Abnormalities of the
RB1 gene can lead to a type of eye
cancer (retinoblastoma) in infants, as
well as to other cancers.
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Genes that repair DNA
A second group of tumor
suppressor genes is responsible for
repairing DNA damage. Every time a
cell prepares to divide into 2 new
cells, it must duplicate its DNA.
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This process is not perfect, and
copying errors sometimes occur.
Fortunately, cells have DNA repair
genes, which make proteins that
proofread DNA. But if the genes
responsible for the repair are faulty,
then the DNA can develop
abnormalities that may lead to
cancer.
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Cell "suicide" genes
If there is too much damage to
a cell DNA to be fixed by the DNA
repair genes, the p53 tumor
suppressor gene is responsible for
destroying the cell by a process
sometimes described as "cell
suicide."
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Many sporadic (not inherited)
cancers such as lung cancers, colon
cancers, breast cancers as well as
others often have mutated p53
genes within the tumor.
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Inherited Abnormalities of Tumor
Suppressor Genes
Inherited abnormalities of
tumor suppressor genes have been
found in several cancers that tend to
run in families.
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In addition to mutations in p53,
RB1, and the genes involved in
HNPCC, several other mutations in
tumor suppressor genes can be
inherited.
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A defective APC gene causes
familial polyposis, a condition in
which people develop hundreds or
thousands of colon polyps, some of
which may eventually acquire several
sporadic mutations and turn into
colon cancer.
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Abnormalities of the BRCA genes
account for 5% to 10% of breast
cancers. There are also many other
examples of inherited tumor
suppressor gene mutations, and
more are being discovered each year.
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Oncogene/Tumor
Suppressor Gene
Related Cancers
BRCA1, BRCA2
Breast and ovarian cancer
bcr-abl
Chronic myelogenous leukemia
bcl-2
B-cell lymphoma
HER2/neu (erbB-2)
Breast cancer, ovarian cancer, others
N-myc
Neuroblastoma
EWS
Ewing tumor
C-myc
Burkitt lymphoma, others
p53
Brain tumors, skin cancers, lung cancer, head
and neck cancers, others
MLH1, MSH2
Colorectal cancers
APC
Colorectal cancers
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4. Multi-stage Carcinogenesis
Multi-stage carcinogenesis starts with the
development of initiated cells after interactions of
acarcinogenic agent with normal (target) cells.
The initiated cells have the ability to clonally
expand and act as precursors for additional
alterations. In different model systems initiated
cells have shown some of the following
characteristics.
1. Increased proliferative capabilities
2. Resistance to apoptotic stimuli
3. Resistance to other inducers of cell toxicity
4. Increased life-span
Medical Genetics
Medical Genetics