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Advances in genetics and molecular biology have improved our
knowledge of the inner workings of cells, the basic building blocks of
the body. All living things are made of cells. Complex animals, such as
human beings have billions of cells. Cells work together to form
organs, such as the heart, liver, and skin. Human beings have several
organ systems.
As they better understand cells, scientists have also learned
a great deal about how and why cancers develop. Here we will review how
cells work, how they change to become cancer, and how we may be able to
use these changes to better understand, prevent, and treat cancer.
How do cells know what to do?
Each cell has a control center called a nucleus. The
nucleus contains the information that tells the cell what to do and
when to grow and divide. This information comes in the form of genes,
which are contained in chromosomes.
In the nucleus of most human cells (except for sperm and egg cells),
there are 23 pairs of chromosomes. Chromosomes are passed from parents
to their children. One chromosome of each pair is inherited from the
mother, and the other comes from the father. This is why children look
like their parents, and why they may have a tendency to develop certain
diseases that run in their families.
Within each chromosome, there are many hundreds to thousands
of genes. Genes and chromosomes are made up of long strands of a
substance called DNA
(deoxyribonucleic acid). Each gene is made up of a specific DNA
sequence that contains the code (the instructions) for that gene's
function. Genes tell the cell what to do. Many genes tell the cell to
make a certain protein that has a specific job or function in the body.
Other genes help regulate how much protein that another gene makes.
Each human cell has about 25,000 genes.
A cell uses its genes selectively,that is, it can turn on (or
activate) the genes it needs at the right moment and turn off other
genes that it doesn't need. Turning on some genes and turning off
others is how a cell becomes specialized is how a cell becomes a muscle
cell and not a bone cell, for example. Some genes stay active all the
time to make proteins needed for basic cell functions. Others shut down
when their job is finished and start again later if needed.
Genes, as the basic units of heredity, serve 2 major roles in
cancers: some are part of the development of cancer and others protect
the body from cancer.
What are mutations?
Genes are made up of DNA. The arrangement of the DNA building
blocks (called bases) determines the gene and its function. Mutations
are gene defects. They are abnormal changes in the DNA of a gene.
Mutations involve changes in the arrangement of the bases that make up
a gene. Even a change in just one base in the thousands of bases that
make up a gene can have a major effect.
A mutation can affect the cell in many ways. Some mutations
stop a protein from being made at all. Others may change the protein
that is made so that it no longer works the way it should or it may not
even work at all. Some mutations may cause a gene to be turned on, and
make more of the protein than usual. Some mutations don't have a
noticeable effect, but others may lead to a disease. For example, a
certain mutation in the gene for hemoglobin causes the disease, sickle
cell anemia.
Hereditary mutations
Hereditary
mutations are gene defects that are passed from a parent
to child. Hereditary mutations are present in the egg or sperm that
join during fertilization and develop into a fetus. Because the
mutation is present at the beginning, it exists in all cells of the
body, including reproductive cells (the cells that make sperm in males
or the egg cells in females). This means the mutation can be passed
from generation to generation. These are also called germline mutations.
A hereditary mutation is a major factor in about 5% to 10% of all
cancers.
Some people are more likely to develop cancer than others
simply because they are born with mutations in their genes. To learn
more about this, see our document, Heredity and Cancer.
Acquired mutations
Most cancers are caused by DNA changes that are acquired
during the person's life. These are called acquired, sporadic, or somatic mutations.
An acquired mutation can be caused by things in the environment such as
exposure to radiation or toxins. For most acquired mutations, no
specific cause can be found. Unlike the inherited mutations, an
acquired mutation starts in one cell of the body and is found only in
the offspring of that cell. They are not in every cell of the body.
Because they are not in the reproductive cells, acquired mutations
cannot be passed on to the next generation.
It is important to realize that mutations in our cells happen
all the time. Usually, the cell detects the change and repairs it. If
it can’t be repaired, the cell will get a signal telling it
to die in a process called apoptosis.
But if the cell doesn't die and the mutation is not repaired,
it may lead to a person developing cancer. This is more likely if the
mutation affects a gene involved with cell division or a gene that
normally causes a defective cell to die. Most scientists today believe
that cancer develops in a process that has more than one, and likely
several, mutations. So, even in a person who inherits a mutation, at
least one more mutation is needed to "knock out" that gene (so that it
doesn't function). This acquired mutation is needed before a person
develops a heredity-related cancer. Sometimes acquired mutations in
other genes (such as oncogenes) are needed as well. For a person who is
not born with a mutation, 2 acquired mutations in the same gene are
needed to knock out that gene.
Gene mutations that can lead to cancer
The 2 main types of genes that are now recognized as playing a
role in cancer are oncogenes
and tumor suppressor
genes.
Oncogenes
Most oncogenes are mutations of certain normal genes called proto-oncogenes.
Proto-oncogenes are the "good" genes that normally control what kind of
cell it is and how often it divides. When a proto-oncogene mutates
(changes) into an oncogene, 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.
It may be helpful to think of a cell as a car. For it to work
properly, there need to be ways to control how fast it goes. A
proto-oncogene normally functions in a way that is much like a gas
pedal. It helps the cell grow and divide. An oncogene could be compared
with a gas pedal that is stuck down, which causes the cell to divide
out of control.
As scientists learn more about oncogenes, they may be able to
develop drugs that inhibit or stop them. Some drugs that target
oncogenes are already being used, and more are on the way. This is
discussed in more detail later on in this document.
Inherited mutations of oncogenes
A few cancer syndromes are caused by inherited mutations of
proto-oncogenes that cause the oncogene to be turned on (activated).
For example, multiple endocrine neoplasia type 2 is caused by an
inherited mutation in the gene called RET. People affected by this
syndrome often develop an uncommon thyroid cancer called medullary
cancer of the thyroid. They also develop other tumors, including
pheochromocytoma and nerve tumors. Inherited mutations in the gene
called KIT cause hereditary gastrointestinal stromal tumors (GIST).
Acquired mutations in this same gene cause most cases of GIST. And
inherited mutations in the gene called MET cause hereditary papillary
renal cancer.
Acquired mutations of oncogenes
Most cancer causing mutations involving oncogenes are
acquired, not inherited. They generally activate oncogenes by
chromosome rearrangements, gene duplication, or mutation. For example,
a chromosome rearrangement leads to formation of the gene called
BCR-ABL. This leads to the disease chronic myeloid leukemia (CML).
Drugs targeting the BCR-ABL gene have been developed and they have
dramatically improved the treatment of CML. Acquired mutations that
activate the KIT gene cause most cases of gastrointestinal stromal
tumor (GIST). This cancer can be treated with drugs that target the KIT
gene, such as imatinib (Gleevec®).
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).
When tumor suppressor
genes don't work properly, cells can grow out of control, which can
lead to cancer. Many different tumor suppressor genes have been
identified, including p53, BRCA1, BRCA2, APC, and RB1.
A tumor suppressor gene is like the brake pedal on a car.It
normally keeps the cell from dividing too quickly just as a brake keeps
a car from going too fast. When something goes wrong with the gene,
such as a mutation, cell division can get out of control.
An important difference between oncogenes and tumor suppressor
genes is that oncogenes result from the activation (turning
on) of
proto-oncogenes, but tumor suppressor genes cause cancer when they are
inactivated
(turned off).
Inherited mutations of tumor suppressor
genes
Inherited abnormalities of tumor suppressor genes have been
found in some family cancer syndromes. They cause certain types of
cancer to run in families. For example, a defective APC gene causes
familial adenomatous
polyposis (FAP), a condition in which people
develop hundreds or even thousands of colon polyps. Often, at least one
of the polyps becomes cancer, leading to colon cancer. There are many
examples of inherited tumor suppressor gene mutations, and more are
being discovered each year. For more information about inherited
mutations and cancer, see our document Heredity and Cancer.
Acquired mutations of tumor suppressor
genes
Tumor suppressor gene mutations have been found in many
cancers. Most of these mutations are acquired, not inherited. For
example, abnormalities of the gene for p53 have been found in more than
50% of human cancers. Acquired mutations (those which happen during a
person’s life) of this gene appear in a wide range of
cancers, including lung, colorectal, and breast cancer. The p53 protein
is involved in the pathway to apoptosis (also called cell suicide or
programmed cell death).
This pathway is turned on when a cell has DNA
damage that can't be repaired. If the gene for p53 is not working
properly, cells with damaged DNA continue to grow and divide. Over time
this can lead to cancer. The gene for p53 is among the most frequently
mutated genes in human cancer. But acquired changes in many other tumor
suppressor genes also contribute to the development of sporadic (not
inherited) cancers.
How can oncogenes and tumor suppressor genes
be used to help prevent cancer?
As mentioned before, some gene changes (mutations) can be
inherited, which can increase your risk of developing cancer. Some
mutations in oncogenes and tumor suppressor genes have been found often
enough to be useful in helping decide which people are at higher risk
for developing certain types of cancers.
If you have family members with certain cancers known to be
caused by genetic mutations, you might find it helpful to know if you
also have the mutation. Genetic testing can be used to look for such
mutations. But if you are thinking about having genetic testing you
need to see a genetic counselor or other genetics professional first.
The testing often costs a lot and a genetic counselor can look at your
family's history to see if it is likely to be worthwhile. And the
results of genetic testing are not always clear cut. The genetic
counselor can help interpret the results so that you know what they
mean to you and your life. The counselor also can help you learn how to
deal with the test results. Finding a genetic mutation can have a major
impact on a person’s life, as well as the lives of other
family members.
If you know that you carry a certain gene mutation, you may be
able to take some steps to minimize your risk. For example, some
patients who find that they carry a gene that gives them a high risk of
colon cancer will start screening when they are younger and may be
screened more often. People with APC gene mutations have a disease
called familial adenomatous polyposis (FAP). These people may have
their colons removed to prevent colon cancer
For more information, see our documents, Genetic Testing: What
You Need to Know and Heredity and Cancer.
How can oncogenes and tumor suppressor genes
be used to help guide treatment of cancer?
In some cases, specific gene changes help predict which
patients are likely to have a better or worse outlook or which patients
are likely to benefit from certain treatments. For example, many years
ago, experts realized that women with breast cancer with cells that
produce too much of the HER2/neu protein had a worse outcome than women
with normal amounts of the protein. Cancers with too much of this
protein did not respond as well to certain chemotherapy drugs (namely,
cyclophosphamide, methotrexate, and fluorouracil), so now other drugs
are used. A drug was also designed to specifically attack cells with
too much HER2/neu. This drug, trastuzumab (Herceptin®),
has
helped improve outcomes for these patients.
Some tests for certain gene mutations are very sensitive in
finding cancer that persists or returns after treatment. For example,
the leukemia cells of patients with chronic myeloid leukemia (CML)
contain a mutated gene called BCR-ABL. Testing for this mutation is
helpful to confirm the diagnosis and then to see if treatment is
working. This testing can also be used to see if the leukemia has
started coming back after treatment. Even when no leukemia cells are
seen on routine testing, the test for the abnormal gene can find a
single remaining cancer cell among one million normal cells. This may
signal that new treatment is needed.
How can oncogenes and tumor suppressor genes
be used to treat cancer?
The discovery and understanding of oncogenes and tumor
suppressor genes has led to the development of new kinds of cancer
therapies. The following are some examples of genes that are cancer
treatment targets. Research in this area is progressing rapidly, and
drugs targeting certain genes and proteins are becoming more available
over time.
Oncogenes
In some cases of breast cancer, the cells make an excess
amount of a protein called HER2/neu. This protein promotes the growth
of cancer cells. Trastuzumab (Herceptin®)
is a drug that sticks
to the HER2/neu protein so that the growth of the cancer cells is
slowed down. It has already been found to be useful in treating women
whose breast cancer cells have abnormalities of this gene and/or its
protein. Studies are currently being done to see if it will be useful
in treating people with other cancers. Another drug that targets the
HER2/neu protein, lapitinib (Tykerb®),
is also available and
others are being tested in clinical trials.
In chronic myeloid leukemia (CML), the cancer cells have a
gene change that brings the oncogene ABL to a place on another
chromosome called BCR. This creates a new gene called, BCR-ABL, that
makes a type of protein called a tyrosine kinase. Drugs have been
created that target the BCR-ABL protein, killing the leukemia cells.
These drugs include imatinib (Gleevec®),
dasatinib
(Sprycel®), and others. They have led to
remission of the
leukemia in most patients treated in the early stages of their disease.
Most gastrointestinal stromal tumors are caused by activation
of the oncogene called KIT. Others are caused by activation of PDGFRA,
another oncogene. The drug imatanib (Gleevec®)
targets both of
these oncogenes, and is able to shrink these tumors and help patients
live longer.
Tumor suppressor genes
Treating problems in tumor suppressor genes is more difficult.
It would mean restoring normal tumor suppressor gene functions.
Although this seems like a logical approach to gene therapy, there are
still several problems to overcome. A major stumbling block lies in how
to get new DNA into the cancer cells. Another problem is that most
cancers have several mutations, so replacing one gene may not be enough
to stop the cancer cells from growing and spreading.
Scientists have attempted to treat some cancers that have
mutations in the p53 gene by inserting normal p53 genes into viruses
and then trying to infect tumor cells with these viruses. Lab tests
have shown that the treated viruses can get into the tumor cells and
restore the normal p53 gene. These cells then grow more slowly than the
other cancer cells. But the overall results were disappointing, and
studies of this drug have been stopped.
Future directions
Many researchers are very optimistic about the future of
cancer therapies using oncogenes and tumor suppressor genes and this
remains a very active area of research. There are many clinical trials
underway today that could lead to better treatments for many types of
cancer.
Additional resources
More information from your American Cancer
Society
We have selected some related information that may also be
helpful to you. These materials may be viewed on our Web site or
ordered from our toll-free number, at 1-800-227-2345.
National organizations and Web sites*
Along with the American Cancer Society, other sources of
information and support include:
Hereditary
Cancer Center (HCC)
Toll-free number: 1-800-648-8133
Web site: http://medicine.creighton.edu/hcc
The purpose of the HCC is to evaluate and identify families at high
risk for a hereditary cancer. Once a family is identified as having a
hereditary cancer syndrome, the family is educated about the syndrome
and specific recommendations for surveillance or early detection are
provided for those family members who carry a cancer-causing gene, or
who prove to have a high risk for having a gene. Publications are also
written for family education.
National Cancer
Institute
Toll-free number: 1-800-4-CANCER (1-800-422-6237)
Web site: www.cancer.gov
Provides accurate, up-to-date information on a variety of
cancer-related topics such as finding support, financial assistance and
other resources; coping with cancer; cancer genetics, etc (click the
“Cancer Topics” tab on the home page). Also has an
Online Cancer Genetics Services Directory to identify professionals who
provide services related to cancer genetics (cancer risk assessment,
genetic counseling, genetic susceptibility testing, and others). The
direct link is www.cancer.gov/search/geneticsservices.
National Society
of Genetic Counselors (NSGC)
Telephone: 312-321-6834
Web site: www.nsgc.org
NSGC Web site offers a Consumer Information link with the following:
- Making Sense of Your Genes: a 24-page guide to genetic
counseling (may be downloaded and printed)
- Directory of genetic counselors: can be searched by your
area
- Five Questions to Ask Before Considering Genetic Testing
(can be downloaded and printed)
- Guide on collecting family history: a helpful tool in
determining possible genetic risks
- FAQs on genetic testing and genetic counselors
*Inclusion on
this list does not imply endorsement by the
American Cancer Society.
No matter who you are, we can help. Contact us anytime, day or
night, for cancer-related information and support. Call us at
1-800-227-2345
or visit www.cancer.org.
References
U.S. Department of Health and Human Services. Understanding
Gene Testing. Available at
http://www.accessexcellence.org/AE/AEPC/NIH/index.html.
Pierotti MA, Sozzi G, Croce CM. Oncogenes. In: Kufe DW,
Pollock RE, Weichselbaum RR, et al, eds. Cancer Medicine.
6th ed.
Hamilton, Ontario: BC Decker Inc; 2003: 73–85.
Park BH, Vogelstein B. Tumor-suppressor genes. In: Kufe DW,
Pollack RE, Weichselbaum RR, et al, eds. Cancer Medicine.
6th ed.
Hamilton, Ontario: BC Decker; 2003: 87–106.
Ringer DP, Schniper LE. Principles of Cancer Biology. In:
Lenhard RE, Osteen RT, Gansler T, eds. Clinical Oncology.
Atlanta, GA:
American Cancer Society; 2001: 25–30.
DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles
and Practice of Oncology. 7th ed. 2008; 157–168.
Tufts University School of Medicine, Department of Anatomy and
Cellular Biology. The somatic mutation theory of cancer: growing
problems with the paradigm? Bioessays.
2004; 26:1097–1107.
Kunstmann E, Vieland J, Brasch FE, et al. HNPCC: Six new
pathogenic mutations. BMC
Med Genet. 2004;5:16.
Reeves, S. New cancer drug uses UT-patented gene therapy
method. The Daily Texan,
9/22/03.
Last Medical Review: 07/08/2009
Last Revised: 07/08/2009
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