Are Women More
to Breast and Ovarian
Cancer If a Mutation in
BRCA1 and BRCA2 is
Breast and Ovarian cancer are the two most common kinds of cancers
found in women in the United States. An estimated 90-95% of cancer cases
are believed to be environmental and lifestyle related. The remaining five to
ten percent of these types of cancers may be caused by inherited genetic
mutations. The existence of a breast cancer susceptibility gene known as
BRCA1 and its approximate location on human chromosome 17 have been
known for about 4 years, on the basis of retrospective family studies. But
only since 1994 have scientist actually been able to isolate and sequence the
gene. In 1995, BRCA2 (a similar gene) was identified. In some families, the
gene is inherited in a mutated form. Women who inherit a mutated form are
highly susceptible to breast and ovarian cancers. BRCA1 and BRCA2 are
two known genes that are responsible for an increased risk of both breast and
ovarian cancer. (Malone 136)
What is cancer? Cancer is defined as a disease in which abnormal
cells multiply without control, destroying healthy tissue and endangering life.
Cancer occurs in most species of animals and in many kinds of plants, as well
as human beings. About 100 types of cancers attack human beings. BRCA1
and BRCA2 are genes linked to breast (male and female), prostate, ovarian,
and colon cancer. (Harris 1)
Cancer strikes people of all ages, but especially middle-aged to elderly
people. It occurs equally among both males and females. The disease can
attack any part of the body and may spread through means of blood flow.
Cancer may spread only if it is not caught in time. Many types of cancers are
determined in various stages in which they can be treated and possibly cured.
The occurrence of a specific kind of cancer varies from country to
country. For example cancer of the stomach is much more common in Japan
than in the United States. The primary body sites that cancer strikes most
often are the skin; the female breasts; and the organs of the digestive,
respiratory, reproductive, blood-forming, lymphatic, and urinary systems.
The body of an adult human being is made up of hundreds of billions of
cells. Each minute, several billion of these die and are replaced several
billion new cells. Each if these new cells then doubles in size and becomes
capable of dicing throughout mitosis. This way, new cells are being produced
for every cell that dies. Normal, non-cancerous cells, divide at a normal rate
required to replace dying cells, never at a faster rate. Like normal cells,
cancer cells reproduce by dividing, but have lost the ability to reproduce at a
controlled rate. (Collins 183)
Whenever anything interferes with the reproductive control of cells, the
cells multiply and gradually build up a mass of tissue called a tumor. Tumors
that are benign do not spread, while tumors that are malignant do spread and
destroy other parts of the body. The spread of cancer from one part of the
body to the other is known as metastasis. Cancer’s ability to spread makes
the disease extremely difficult to treat unless detected early. (Harris 4)
Most experts agree that people develop cancer mainly through
prolonged contact with one or more carcinogens. In addition, scientists
suspect that a person may inherit a tendency to develop the disease as well,
linking it to DNA alterations. Carcinogens attack normal cells and may
eventually cause one of the cells to become cancerous. Scientists believe that
90 to 95% of cancer start this way. The changes are then passed on to the
cell’s descendants. One cancerous cell turns into two, and two into four, and
four into eight, and so on. Carcinogens are introduced into the body through
the nose, mouth, or some other bodily openings. Many cancers are caused by
a combination of two or more agents usually rather than a single one.
Some cancers, including those of the breast and colon, occur among
blood relatives at a higher than average rate. Scientist believe that some
people inherit a tendency to develop a certain type of cancer. Only a few
types of cancer though have been proven to be hereditary, such as, breast and
ovarian cancer. In addition researchers have identified certain genes, called
proto-oncogenes, that are vital to early tissue development. When these
genes become changed or rearranged by chemicals or viruses, these genes in
their altered state are called oncogenes. The oncogenes than transform a
healthy cell into a cancerous cell. Scientists have identified over 50
oncogenes that may cause cancer in certain organs such as the bladder,
breasts, liver, lungs, colon, and pancreas. Some scientists believe that
oncogenes are involved in all cancers, while others do not. (Harris 7)
Breast cancer is one of the most common types of cancer among
American women, affecting 1 in 10 during their life time. It is estimated that
45% of all families with significantly high breast cancer incidence, and at
least 80% of families with elevated rates of both early-onset breast cancer and
ovarian cancer, carry the mutated BRCA1 gene. A rough estimate is that 1 in
200 women in the U.S may have an inherited mutation in the gene. (American
Cancer Society packet)
Up until the 1940’s many doctors and scientist thought breast cancer
was a result of old aging. Scientists know now that breast cancer is not a
result of old aging, but a result of being in contact with too many carcinogens,
or as a result of inheriting certain genes. It is becoming more and more clear,
that all cancers i.e. breast cancer, have a strong genetic basis, not necessary
meaning that they are all hereditary, but can be found linked to certain genes
on chromosomes. (Love 165)
Normal cells have 46 chromosomes which appear in 23 pair, but
cancer cells usually have many more and on occasion fewer. The risks of
developing breast cancer comes from either parent. Because each person has
two copies of each gene, but transmits only one copy to each of his or her
offspring, the laws of chance predict that about half of all children of a parent
with a mutation in the BRCA1 gene will inherit the alteration. This flawed
gene will make you more susceptible to cancer. The most common genes in
women and men, that when damaged cause breast cancer are BRCA1 and
BRCA2. BRCA1 and BRCA2 are also linked to an increased risk for ovarian
cancer as well as breast cancer. (Love 167)
Usually breast and ovarian cancer are not inherited. It has been
estimated that about 5 to 10% of all breast and ovarian cancers are thought to
be due to mutations in a gene inherited from a parent. However, if an
individual has several closely related family members with breast and/or
ovarian cancer, or if cancer has occurred at an early age, there is higher
suspicion that the breast cancer in that family may be an inheritance.
BRCA1: BR=breast CA=cancer gene 1, located on chromosome 17q,
was first discovered in 1994 by Mark Skolnick at Myriad Genetics Corp.
BRCA1 normally is responsible for making proteins which is important for
the normal functions of the cells. A mutation in BRCA1 can change the
protein it makes so the protein does not work as well. The BRCA1 gene is
encoded by 5591 nucleotides distributed over a gnomic region which is
approximately 100kb in length. (Langston 3) SEE DIAGRAM 1
It is possible that the BRCA1 gene may be involved in some sporadic
cases through somatic mutations (mutations that cannot be passed to
offspring) that occur in DNA of breast cells during a woman’s lifetime.
Preliminary evidence, however, suggests that BRCA1 plays a small role, if
any, in sporadic breast cancer. (Langston 4)
BRCA2: BR=breast CA=cancer gene 2 was discovered in 1995 by Dr.
Steven Narod in Ontario, Canada. Twenty-two coding exons of the gene
encode a protein of 1863 amino acids. The protein contains a putative RING
finger domain near the amino-terminal, suggesting BRCA2 may regulate
transcription. (Levine 25) DIAGRAM 1
BRCA2, located on chromosome 13q, functions similar to BRCA1.
The only real difference between BRCA1 and BRCA2 is that BRCA2
increases the risk for male cancer, while BRCA1 does not. Also the
estimated risk of ovarian cancer with BRCA2 is not as high as BRCA1.
When researchers isolated these gene, they looked at selected
individuals with either breast and/or ovarian cancer. The researchers who
isolated the gene looked for BRCA1 mutations in 32 breast tumors and 12
ovarian tumors from patients who were not known to be members of
cancer-prone families. From this test scientists found BRCA1 mutations in
three of the breast tumors and in one of the ovarian tumors. However, each
of the four was found to be a germline mutation, which suggests that these
patients have inherited a BRCA1 gene mutation in the same way as women
from the families that have been studied. Future research will clarify if
BRCA1 has any role in sporadic breast cancers. Studies of families with
inherited alterations in BRCA1 has suggested that more than half the women
who carry a cancer associated mutation in the gene will be diagnosed with
breast cancer by age 50. (American Can Soc Pack 3)
Since the isolation of these genes, studies characterizing the effects of
specific mutations are presently being conducted. Existing tests to determine
whether a person carries a BRCA1 mutation are effected on both research on
commercial levels. Once the gene is identified in a family, researchers can
look directly for the specific mutation. This allows testing for family
members to be much more easy, as well as less expensive. (Rizzler 24)
In women who have been found to carry an altered BRCA1 gene, the
risk to develop breast cancer by age 70 may be as high as 80.5% and the risk
for ovarian cancer 40 to 60%. In other words, out of a 100 women who
inherit BRCA1 mutations, about 80 will develop cancer by the time they
reach 70 years; about 40-60 women will develop ovarian cancer. For women
who develop cancer in one of the breasts, the risk is increased for cancer to
develop in the other breast as well. Men who carry a mutation in BRCA1 do
not seem to have high risk to develop breast cancer, but there may be a
slightly increased risk for prostate cancer or colon cancer. (Bre Ova
We all have two BRCA1 and BRCA2 genes. We get these genes from
both our mother and our father. A mutation in either of these genes can be
inherited from either parent. If the mother or father does have a mutation then
each of his or her children has a 50% chance of inheriting the mutation.
Chance determines who inherits the gene and who does not, and the
appearance of the gene in one child has no effect on the risk in other children
in the family. It is possible that all or none of the offspring of an affected
parent will inherit the mutated gene. (Scalia 1) SEE DIAGRAM 2
BRCA1 and BRCA2 in their natural form, are thought to be important
for normal function of cells. Because BRCA1 is a gene that has recently been
identified, little is known either of its role in breast cancer development or its
normal function. If there is a mutation, however, in either of these genes, or
one copy of either gene is lost or damaged, its function may be disrupted,
making breast cells and ovarian cells more prone to the susceptibility of
developing cancer. Not everyone who inherits a mutation in BRCA1 and
BRCA2 develops breast or ovarian cancer. BRCA1 or BRCA2 mutation
does not cause cancer; however it does increase the chances for a person to
develop cancer. Scientists do not know why only some individuals with a
mutation develop cancer and why some do not, however, with the rapid
progression of cancer research and genetic testing these questions may soon
be resolved. (Scalia 1)
Everyone has two genes of a specific trait. One from mom and one
from dad. If one of these genes becomes mutated, or lost, then the other can
serve as a break for the other and continue to function as normal. Women
with inherited BRCA1 mutation are born with one bad copy, so that for
cancer to occur they need only one additional damaging mutation in a breast
cell some time during life. It is suspected that the BRCA1 and BRCA2 genes
function as a tumor suppressor. Suppressor genes normally prevent
uncontrolled cell proliferation and their inactivation through mutation can lead
to cancer. Inherited mutation occurs only on one gene, while the other is not
effected. Chances of that person developing cancer from one of these genes
is greatly increased, i.e. 85% breast cancer and 50% for ovarian cancer.
(Scalia) SEE DIAGRAM 3 & 4
One study published in the March 19, 1994 issue of the Lancet
suggested that more than 40% of women with a mutated BRCA1 gene may
develop ovarian cancer. Also in this study, both male and female carriers of
BRCA1 mutations had significantly elevated risks of colon cancer, and male
carriers had increased risk of prostate cancer. (American Cancer Society)
Only about half (45%) of all inherited breast cancers is due to
mutations in BRCA1. About 35% is due to mutations in BRCA2. There may
be other genes which increase the risks for developing breast cancer as well.
Scientists speculate there might even be a BRCA3 and a BRCA4 gene. Right
now scientists do know of two other genes, tP53 and ATM, that might cause
a person to develop breast cancer; tP53 is involved in breast cancer
development only when a person has the Li-Fraumency syndrome. Scientists
know little about these genes and do speculate that ATM only effects the
breast tissue in combination with certain syndromes. (Cummings pg. 5)
By studying normal cells and cancer cells under microscopes, cell
biologists have discovered important differences in the cell’s behavior. They
have found that during the process of mitosis, a series of carefully
orchestrated steps, normal cells continue dividing until they come in contact
with neighboring cells. Cell division then stops. This characteristic of normal
cells is called contact inhibition. Cells that develop cancer have lost contact
inhibition. They continue to divide even after they have come into contact
with other cells. (Kormanicky 56)
BRCA1 and mRNA levels were found invariably low in tumors from
BRCA1 mutations carriers. As a tumor grows it needs nourishment. The
tumor sends out protein messengers called tumor aniogene factors to get the
material it needs. Normal breast epithelium surrounding the BRCA1 tumors
showed higher mRNA levels than tumor tissue, indicating that the low mRNA
levels were due to somatic inactivation of the wild-type BRCA1 gene.
Cell biologists have developed methods of destroying cancer cells
without damaging healthy cells. They are also trying to learn how
cancer-causing oncogenes are activated and how they can be turned off. If
scientists learn how to deactivate oncogenes, they may find ways of
controlling the reproduction of a cancer cells. Such type of genes that may be
able to turn off are BRCA1 and BRCA2. The process on how one would turn
these genes off is still not devised yet. (Myriad Genetics Patient pamphlet)
When BRCA1 or BRCA2 mutation is inherited it is considered a
dominant factor. People receive one BRCA1 allele from their mom and one
BRCA1 allele from their dad. The same goes for any other gene pairs.
BRCA1 is not just inherited by women, but men as well. It is NOT a
sex-linked trait. In order to study how organisms inherit genes, health care
professionals use a Punnet square in order to understand how people inherit a
gene. Finding out if a person does have a BRCA1 or BRCA2 mutation is
another process. (Myriad Genetic Pamphlet) DIAGRAM 5
Inherited alleles of family tumor suppressor gene predispose
individuals to particular types of cancer; this is one of the reasons why cancer
occurs. Doctors are still not sure what causes BRCA1 and BRCA2 genes to
mutate. In addition to trying to find mutations on the BRCA1 and BRCA2
genes, doctors are telling people to stay healthy in order to decrease a
person’s risk of cancer. Some mutations not on BRCA1 and BRCA2 stop the
gene from functioning, while others force genes to create abbreviated or
misshapen molecules (proteins) that function incorrectly. (Travis 374)
The risk of harboring a mutation is not limited to women who have a
family history of breast or ovarian cancer. Results of this represent a minimal
estimate of the frequency of BRCA1 mutations. Right now scientists have
found over 100 distinct germ-line mutations of BRCA1 that have been
identified in more than 100 patients with breast/ovarian cancer. A recent
collaborative survey describing 80 germ-line mutations summarizes the
spectrum and frequency of BRCA1 mutations identified to date primary in the
high-risk families. (Langston 3)
No somatic mutations of the BRCA1 or BRCA2 genes have been
identified in sporadic breast cancers, though 5 mutations have been found in
sporadic ovarian tumors. This suggest that BRCA1 is primarily a germ-line
mutation. (Gaithersburg 1)
The outcome of BRCA1 mutations may reflect the different duties the
gene’s protein performs in breast and ovarian cells. Scientists think that
there are only 3 main types of mutations on BRCA1. Additional mutations
have been found twice by a complete screening of the cDNA. The total
percent of a recurring mutations is 31%. (Davison www.cancer.org)
Inherited mutations on BRCA1 and BRCA2 are known to contribute to
a predisposition to breast cancer. Heterozygotes for mutations in the
ataxia-telangiectasia gene also increases a woman’s risk for breast cancer.
Females who are obligated carriers of ataxia telangiectasia have a 4 to 12
times increased relative risk of developing breast cancer as compared to the
general female population. Increasing their overall chances of developing
breast cancer. (Anderson 408)
Mutations in the BRCA1 gene are identified through a highly technical
process; the sequencing of DNA obtained from a blood sample. Currently
Myriad Genetic Laboratories is testing individuals under clinical research
protocols with institutional review board approval. The decision to be tested
must be made by the individual, in consultation with a healthcare
professional. Those who may benefit form the BRCA1 genetic susceptibility
testing include: (American Can Soc 13)
~women who have been diagnosed with breast cancer, especially those
with early onset-disease.
~women who have been diagnosed with ovarian cancer.
~women with a family history of either breast or ovarian cancer.
~women who are blood relatives of those who carry a BRCA1
~men who are blood relatives of those who carry a BRCA1 mutation.
If the family history of a woman with breast/ovarian cancer is uncertain
or unknown, testing may still be appropriate. For example, she may have few
female relatives or, since men also have a 50% chance of passing the
mutation to each of their offspring, the susceptibility may have been passed
through her paternal line. These and other factors need to be considered in
the woman’s decision to be tested. (Ovarian Cancer Pamphlet)
Early cancer detection provides the best opportunity for reducing
mortality for all women. Women who test positive for BRCA1 genetic
susceptibility may benefit from increased surveillance. Some healthcare
professionals are prescribing earlier implementation and more frequent
utilization of the following surveillance methods: (Ovarian Cancer Pamphlet)
Breast cancer detection guidelines:
~clinical breast exams.
~consultation with a qualified healthcare professional if a change in
breast tissue is detected.
Ovarian cancer guidelines:
~CA-125 serum tumor marker testing
~rectovaginal pelvic examination
Women who have a BRCA1 mutation and have been diagnosed with
breast cancer are at an increased risk of developing cancer in the other breast.
This may affect treatment decisions, i.e., the choice between a mastectomy or
a lumpectomy of the affected breast, and either prophylactic mastectomy of
the unaffected breast and/or prophylactic oophorectomy. (Doctor Pamphlet
on breast cancer/Gaitherburg)
Ways to treat breast cancer:
~Prophylactic oophorectomy. Many clinicians believe that this is the
treatment of choice for the women who carry BRCA1 mutation or for those
who have a strong family history of breast cancer. A bilateral removal of the
ovaries to decrease estrogen production is effective as well. Other
considerations include the individual’s risk for cardiovascular disease and
osteoporosis and her concerns about sterility. (Doctors Pamphlet on BRCA1
~Prophylactic mastectomy. Because dense breast tissue may interfere with
the clinical examination and mammography, and in premenopausal women
every breast cell has a mutated gene placing a woman at a 95% risk during
her lifetime for breast cancer, the volume of the breast tissue that can be
affected is reduced through mastectomy, making prophylactic surgery
appropriate for women who carry a BRCA1 mutation. However, because
surgery cannot remove all breast tissue, the risk of developing breast cancer
cannot be totally eliminated. (Doctors Pamphlet on BRCA1 and 2)
Another kind of treatment is hormone replacement therapy.
Hormone replacement therapy has been shown to be effective in relieving
some of the conditions often associated with menopause, as well as
decreasing the risk of a heart attack and osteoporosis. However, the use of
replacement hormones may increase the risk of breast and endometrial
cancer. Post menopausal women who are currently taking hormones
(estrogen or a combination of estrogen and progesterone) have a relative risk
of 1.46% of developing breast cancer compared to post-menopausal women
who have never taken hormones or had breast cancer. The effect of hormone
replacement therapy for shorter periods of time and for women who carry a
mutated BRCA1 gene is currently unknown. (Gayther 1462)
There are some life modifications that women can make in order to
decrease their chance of breast cancer. Women who carry a BRCA1
mutation should be encouraged to evaluate their current lifestyle habits and, if
necessary and/or appropriate, modify the following: (Gross 88)
Age at first pregnancy: Data indicates that women who deliver their
first child before age 30 are less likely to develop breast and ovarian cancer.
Body weight: individuals who are 40% or more over- weight may
have an increased risk of breast and ovarian cancer. In addition, maintaining
desirable body weight increases efficacy of cancer screening procedures.
Exercise: Physical activity during a woman’s reproductive years
affect the production of estrogen and other sex hormones. This may provide
a protective effect against breast cancer risk.
Tobacco use: A study indicates that a woman’s risk of dying from
breast cancer increases 25% if the women smokes cigarettes.
Diet: Some studies suggest that eating a balanced diet has an
anti-tumor affect. Recommendations for a balanced diet include foods low in
fat and rich in fiber and antioxidants; green leafy vegetables; soy products;
and broccoli, cabbage, brussel sprouts, and other cruciferous vegetables.
Alcohol: Some studies indicate there is some link between alcohol
consumption and the development of breast cancer, although no causal
relationship has not been proven. (Gross 89) SEE DIAGRAM 6
In the future, scientists hope discoveries will lead to gene therapy, but
for now there is little one can do about a genetic predisposition beyond
counseling and lifestyle changes. The BRCA1/BRCA2 genetic susceptibility
test is commercially available through Myriad Genetic and OncorMed
Laboratories. Testing to verify sensitivity, specificity, and other parameters
will commence at cancer centers throughout the U.S. Educational materials
will be provided to healthcare professionals who offer BRCA1/BRCA2
testing to assist in presenting and discussing issues with patients both before
and after the test. (Breast/Ovarian Pamphlet)
Having a test for either BRCA1 or BRCA2 could affect a person’s
ability to get or to keep insurance in the future. If a mutation is found in
someone’s family that increases the risk for developing cancer, it could affect
their family’s ability to get or to keep insurance (health, life, and disability).
One may experience loss of insurance, inability to qualify for new insurance,
increased premium payments, or decreased coverage. A person may be
locked into a job to keep coverage, or lose coverage in the event of a job loss.
(Hereditary Breast Cancer 4)
Patients should talk to their doctor about how the information will be
kept in their medical record. People who are concerned about how their test
results will be used need to consider paying for tests out of their own
pockets. Legislators are in the process of introducing state bills which ban
such discrimination from employers and insurance companies. Twenty states
already have statutes that, to varying degrees, protect the confidentiality of
genetic test results and protect them from employment or insurance
The presence of a mutation in BRCA1 or BRCA2 indicates that there
is a risk to develop cancer. It does not mean that cancer will definitely
develop. Although testing is very accurate, there is a chance that an inherited
mutation in BRCA1 or BRCA2 will not be detected or that a mutation exists
in another gene for which testing was not done. Cancer can and does occur
for other reasons… (Hereditary Breast Cancer 4)
There are psychological risks for being tested. Some people may also
have difficulty in knowing that they carry a gene which increases their risk to
develop breast cancer. They may experience emotions, such as: anger,
denial, anxiety, or shock; fear of cancer or of the future; worry about their
health, family, employability; changed self-image; guilt for possibly passing
the gene to children; worry about the future medical costs and insurability.
These are all normal reactions. (Hereditary Breast Cancer 4)
If a mutation in BRCA1 and BRCA1 is found, one will be encouraged
to inform other family members who may also carry the mutation. In the
process, other family members may also find out confidential information.
For example, someone may disclose that a family member is adopted.
Therefore, sometimes relationships in families may be affected. (Hereditary
Breast Cancer 4)
In conclusion, it is believed that 1 out of 3 women will inherit breast
cancer during their life time, though others may disagree. Undoubtedly breast
cancer is a silent killer in which it must be detected early in order to be
prevented or stopped. As one person put it, ?This is the most exciting and
most frightening time there is in the research of breast cancer.?
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