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_BRCA1 &BRCA2 _
By: jamie smith
Are Women More Susceptible to Breast and Ovarian Cancer If a Mutation in BRCA1
and BRCA2 is Found 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. (Harris 2) 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.
(Harris 2) 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. (Harris 7) 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. (Scalia 1) 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. (Langston 3) 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 PAMPHLET) 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. (Komanicky 56) 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 mutation ~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: ~breast self-exams ~clinical breast
exams ~mammograms ~consultation with a qualified healthcare professional
if a change in breast tissue is detected. Ovarian cancer guidelines:
~CA-125 serum tumor marker testing ~transvaginal ultrasound ~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 and 2) ~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 discrimination
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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