- What are BRCA1 and BRCA2?
BRCA1 and BRCA2 are human genes that belong to a class
of genes known as tumor suppressors.
In normal cells, BRCA1 and BRCA2 help ensure the stability
of the cell’s genetic material (DNA) and help prevent uncontrolled cell
growth. Mutation of these genes has been linked to the development of hereditary
breast and ovarian cancer.
The names BRCA1 and BRCA2 stand for breast
cancer susceptibility gene 1
and breast cancer susceptibility
gene 2, respectively.
- How do BRCA1 and BRCA2
gene mutations affect a person's risk of cancer?
Not all gene changes, or mutations, are deleterious (harmful). Some mutations
may be beneficial, whereas others may have no obvious effect (neutral). Harmful
mutations can increase a person’s risk of developing a disease, such
as cancer.
A woman’s lifetime risk of developing breast and/or ovarian cancer
is greatly increased if she inherits a harmful mutation in BRCA1
or BRCA2. Such a woman has an increased risk of developing breast
and/or ovarian cancer at an early age (before menopause) and often has multiple,
close family members who have been diagnosed with these diseases. Harmful
BRCA1 mutations may also increase a woman’s risk of developing
cervical, uterine, pancreatic, and colon cancer (1, 2).
Harmful BRCA2 mutations may additionally increase the risk of pancreatic
cancer, stomach cancer, gallbladder and bile duct cancer, and melanoma (3).
Men with harmful BRCA1 mutations also have an increased risk of
breast cancer and, possibly, of pancreatic cancer, testicular cancer, and
early-onset prostate cancer. However, male breast cancer, pancreatic cancer,
and prostate cancer appear to be more strongly associated with BRCA2
gene mutations (2–4).
The likelihood that a breast and/or ovarian cancer is associated with a harmful
mutation in BRCA1 or BRCA2 is highest in families with a
history of multiple cases of breast cancer, cases of both breast and ovarian
cancer, one or more family members with two primary cancers (original tumors
that develop at different sites in the body), or an Ashkenazi (Eastern European)
Jewish background (see Question 6). However, not
every woman in such families carries a harmful BRCA1
or BRCA2 mutation, and not every cancer in
such families is linked to a harmful mutation in one of these genes. Furthermore,
not every woman who has a harmful BRCA1 or
BRCA2 mutation will develop breast and/or ovarian cancer.
According to estimates of lifetime risk, about 12.0 percent of women (120
out of 1,000) in the general population will develop breast cancer sometime
during their lives compared with about 60 percent of women (600 out of 1,000)
who have inherited a harmful mutation in BRCA1 or BRCA2
(4, 5). In other words, a woman who has
inherited a harmful mutation in BRCA1 or BRCA2 is about
five times more likely to develop breast cancer than a woman who does not
have such a mutation.
Lifetime risk estimates for ovarian cancer among women in the general population
indicate that 1.4 percent (14 out of 1,000) will be diagnosed with ovarian
cancer compared with 15 to 40 percent of women (150–400 out of 1,000)
who have a harmful BRCA1 or BRCA2 mutation (4,
5).
It is important to note, however, that most research related to BRCA1
and BRCA2 has been done on large families with many individuals affected
by cancer. Estimates of breast and ovarian cancer risk associated with BRCA1
and BRCA2 mutations have been calculated from studies of these families.
Because family members share a proportion of their genes and, often, their
environment, it is possible that the large number of cancer cases seen in
these families may be due in part to other genetic or environmental factors.
Therefore, risk estimates that are based on families with many affected members
may not accurately reflect the levels of risk for BRCA1 and BRCA2
mutation carriers in the general population. In addition, no data are available
from long-term studies of the general population comparing cancer risk in
women who have harmful BRCA1 or BRCA2 mutations with women
who do not have such mutations. Therefore, the percentages given above are
estimates that may change as more data become available.
- Do inherited mutations in other genes increase
the risk of breast and/or ovarian tumors?
Yes. Mutations in several other genes, including TP53, PTEN, STK11/LKB1,
CDH1, CHEK2, ATM, MLH1, and MSH2, have been associated with
hereditary breast and/or ovarian tumors (4, 6,
7). However, the majority of hereditary breast cancers can
be accounted for by inherited mutations in BRCA1 and BRCA2
(8). Overall, it has been estimated that inherited BRCA1 and BRCA2
mutations account for 5 to 10 percent of breast cancers and 10 to 15 percent
of ovarian cancers among white women in the United States (6).
- Are specific mutations in BRCA1
and BRCA2 more common in certain populations?
Yes. For example, three specific mutations, two in the BRCA1 gene
and one in the BRCA2 gene, are the most common mutations found in
these genes in the Ashkenazi Jewish population. In one study, 2.3 percent
of participants (120 out of 5,318) carried one of these three mutations (9).
This frequency is about five times higher than that found in the general population
(10). It is not known whether the increased frequency of
these mutations is responsible for the increased risk of breast cancer in
Jewish populations compared with non-Jewish populations.
Other ethnic and geographic populations around the world, such as the Norwegian,
Dutch, and Icelandic peoples, also have higher frequencies of specific BRCA1
and BRCA2 mutations.
In addition, limited data indicate that the frequencies of specific BRCA1
and BRCA2 mutations may vary among individual racial and ethnic groups
in the United States, including African Americans, Hispanics, Asian Americans,
and non-Hispanic whites (11–13).
This information about genetic differences between racial and ethnic groups
may help health care providers in selecting the most appropriate genetic test(s)
(see Question 5).
- Are genetic tests available to detect BRCA1
and BRCA2 mutations, and how are they performed?
Yes. Several methods are available to test for BRCA1 and BRCA2
mutations (14). Most of these methods look for changes
in BRCA1 and BRCA2 DNA. At least one method looks for changes
in the proteins produced by these genes. Frequently, a combination of methods
is used.
A blood sample is needed for these tests. The blood is drawn in a laboratory,
doctor's office, hospital, or clinic and then sent to a laboratory that specializes
in the tests. It usually takes several weeks or longer to get the test results.
Individuals who decide to get tested should check with their health care provider
to find out when their test results might be available.
Genetic counseling is generally recommended before and after a genetic test.
This counseling should be performed by a health care professional who is experienced
in cancer genetics (see
Question 17). Genetic counseling usually involves
a risk assessment based on the individual’s personal and family medical
history and discussions about the appropriateness of genetic testing, the
specific test(s) that might be used and the technical accuracy of the test(s),
the medical implications of a positive or a negative test result, the possibility
that a test result might not be informative (an ambiguous result) (see below),
the psychological risks and benefits of genetic test results, and the risk
of passing a mutation to children.
- How do people know if they should consider
genetic testing for BRCA1 and BRCA2 mutations?
Currently, there are no standard criteria for recommending or referring someone
for BRCA1 or BRCA2 mutation testing.
In a family with a history of breast and/or ovarian cancer, it may be most
informative to first test a family member who has breast or ovarian cancer.
If that person is found to have a harmful BRCA1 or BRCA2
mutation, then other family members can be tested to see if they also have
the mutation.
Regardless, women who have a relative with a harmful BRCA1 or BRCA2
mutation and women who appear to be at increased risk of breast and/or ovarian
cancer because of their family history should consider genetic counseling
to learn more about their potential risks and about BRCA1 and BRCA2
genetic tests.
The likelihood of a harmful mutation in BRCA1 or BRCA2
is increased with certain familial patterns of cancer. These patterns include
the following (15):
- For women who are not of Ashkenazi Jewish descent:
- two first-degree relatives (mother, daughter, or sister) diagnosed
with breast cancer, one of whom was diagnosed at age 50 or younger;
- three or more first-degree or second-degree (grandmother or aunt)
relatives diagnosed with breast cancer regardless of their age at diagnosis;
- a combination of first- and second-degree relatives diagnosed with
breast cancer and ovarian cancer (one cancer type per person);
- a first-degree relative with cancer diagnosed in both breasts (bilateral
breast cancer);
- a combination of two or more first- or second-degree relatives diagnosed
with ovarian cancer regardless of age at diagnosis;
- a first- or second-degree relative diagnosed with both breast and
ovarian cancer regardless of age at diagnosis; and
- breast cancer diagnosed in a male relative.
- For women of Ashkenazi Jewish descent:
- any first-degree relative diagnosed with breast or ovarian cancer;
and
- two second-degree relatives on the same side of the family diagnosed
with breast or ovarian cancer.
These family history patterns apply to about 2 percent of adult women in
the general population. Women who have none of these family history patterns
have a low probability of having a harmful BRCA1 or BRCA2
mutation.
- How much does BRCA1 and BRCA2
mutation testing cost?
The cost for BRCA1 and BRCA2 mutation testing usually ranges
from several hundred to several thousand dollars. Insurance policies vary
with regard to whether or not the cost of testing is covered. People who are
considering BRCA1 and BRCA2 mutation testing may want to
find out about their insurance company’s policies regarding genetic
tests.
- What does a positive BRCA1 or BRCA2
test result mean?
A positive test result generally indicates that a person has inherited a
known harmful mutation in BRCA1 or BRCA2 and, therefore,
has an increased risk of developing certain cancers, as described above. However,
a positive test result provides information only about a person’s risk
of developing cancer. It cannot tell whether an individual will actually develop
cancer or when. Not all women who inherit a harmful
BRCA1 or BRCA2 mutation will develop breast or ovarian cancer.
A positive genetic test result may have important health and social implications
for family members, including future generations. Unlike most other medical
tests, genetic tests can reveal information not only about the person being
tested but also about that person’s relatives. Both men and women who
inherit harmful BRCA1 or BRCA2 mutations, whether they develop
cancer themselves or not, may pass the mutations on to their sons and daughters.
However, not all children of people who have a harmful
mutation will inherit the mutation.
- What does a negative BRCA1 or BRCA2
test result mean?
How a negative test result will be interpreted depends on whether or not
someone in the tested person’s family is known to carry a harmful BRCA1
or BRCA2 mutation. If someone in the family has a known mutation,
testing other family members for the same mutation can provide information
about their cancer risk. If a person tests negative for a known mutation in
his or her family, it is unlikely that they have an inherited susceptibility
to cancer associated with BRCA1 or BRCA2. Such a test result
is called a “true negative.” Having a true negative test result
does not mean that a person will not develop cancer; it means that the person’s
risk of cancer is probably the same as that of people in the general population.
In cases in which a family has a history of breast and/or ovarian cancer
and no known mutation in BRCA1 or BRCA2 has been previously
identified, a negative test result is not informative. It is not possible
to tell whether an individual has a harmful BRCA1 or BRCA2
mutation that was not detected by testing (a “false negative”)
or whether the result is a true negative. In addition, it is possible for
people to have a mutation in a gene other than BRCA1 or BRCA2
that increases their cancer risk but is not detectable by the test(s) used.
- What does an ambiguous BRCA1 or
BRCA2 test result mean?
If genetic testing shows a change in BRCA1 or BRCA2 that
has not been previously associated with cancer in other people, the person’s
test result may be interpreted as “ambiguous” (uncertain). One
study found that 10 percent of women who underwent BRCA1 and BRCA2
mutation testing had this type of ambiguous result (16).
Because everyone has genetic differences that are not associated with an
increased risk of disease, it is sometimes not known whether a specific DNA
change affects a person’s risk of developing cancer. As more research
is conducted and more people are tested for BRCA1 or BRCA2
changes, scientists will learn more about these changes and cancer risk.
- What are the options for a person who has
a positive test result?
Several options are available for managing cancer risk in individuals who
have a harmful BRCA1 or BRCA2 mutation. However, high-quality
data on the effectiveness of these options are limited.
- Surveillance—Surveillance means cancer screening,
or a way of detecting the disease early. Screening does not, however, change
the risk of developing cancer. The goal is to find cancer early, when it
may be most treatable.
Surveillance methods for breast cancer may include mammography and clinical
breast exams. Studies are currently under way to test the effectiveness
of other breast cancer screening methods, such as magnetic resonance imaging
(MRI), in women with BRCA1 or BRCA2 mutations. With careful
surveillance, many breast cancers will be diagnosed early enough to be successfully
treated.
For ovarian cancer, surveillance methods may include transvaginal ultrasound,
blood tests for CA–125 antigen, and clinical exams. Surveillance can sometimes
find ovarian cancer at an early stage, but it is uncertain whether these
methods can help reduce a woman's chance of dying from this disease.
- Prophylactic Surgery—This type of surgery involves
removing as much of the "at-risk" tissue as possible in order to reduce
the chance of developing cancer. Bilateral prophylactic mastectomy (removal
of healthy breasts) and prophylactic salpingo-oophorectomy (removal of healthy
fallopian tubes and ovaries) do not, however, offer a guarantee against
developing cancer. Because not all at-risk tissue can be removed by these
procedures, some women have developed breast cancer, ovarian cancer, or
primary peritoneal carcinomatosis (a type of cancer similar to ovarian cancer)
even after prophylactic surgery. In addition, some evidence suggests that
the amount of protection salpingo-oophorectomy provides against the development
of breast and ovarian cancer may differ between carriers of BRCA1
and BRCA2 mutations (17).
- Risk Avoidance—Certain behaviors have been associated
with breast and ovarian cancer risk in the general population (see
Question 16). Research results on the benefits of modifying individual behaviors
to reduce the risk of developing cancer among BRCA1 or BRCA2
mutation carriers are limited.
- Chemoprevention—This approach involves the use
of natural or synthetic substances to reduce the risk of developing cancer
or to reduce the chance that cancer will come back. For example, the drug
tamoxifen has been shown in numerous clinical studies to reduce the risk
of developing breast cancer by about 50 percent in women who are at increased
risk of this disease and to reduce the recurrence of breast cancer in women
undergoing treatment for a previously diagnosed breast tumor. As a result,
tamoxifen was approved by the U.S. Food and Drug Administration (FDA) as
a breast cancer treatment and to reduce the risk of breast cancer development
in premenopausal and postmenopausal women who are at increased risk of this
disease. Few studies, however, have evaluated the effectiveness of tamoxifen
in women with BRCA1 or BRCA2 mutations. Data from three
studies suggest that tamoxifen may be able to help lower the risk of breast
cancer in BRCA1 and BRCA2 mutation carriers (18–20).
Two of these studies examined the effectiveness of tamoxifen in helping
to reduce the development of cancer in the opposite breast of women undergoing
treatment for an initial breast cancer (19, 20).
Another drug, raloxifene, was shown in a large clinical trial sponsored
by the National Cancer Institute (NCI) to reduce the risk of developing
invasive breast cancer in postmenopausal women at increased risk of this
disease by about the same amount as tamoxifen. As a result, raloxifene
was approved by the FDA for breast cancer risk reduction in postmenopausal
women. Since tamoxifen and raloxifene inhibit the growth of breast cancer
cells in similar ways, raloxifene may be able to help reduce breast cancer
risk in postmenopausal BRCA1 and BRCA2 mutation carriers.
However, this has not been studied directly.
- What are some of the benefits of genetic
testing for breast and ovarian cancer risk?
There can be benefits to genetic testing, whether a person receives a positive
or a negative result. The potential benefits of a negative result include
a sense of relief and the possibility that special preventive checkups, tests,
or surgeries may not be needed. A positive test result can bring relief from
uncertainty and allow people to make informed decisions about their future,
including taking steps to reduce their cancer risk. In addition, many people
who have a positive test result may be able to participate in medical research
that could, in the long run, help reduce deaths from breast cancer.
- What are some of the risks of genetic testing
for breast and ovarian cancer risk?
The direct medical risks, or harms, of genetic testing are very small, but
test results may have an effect on a person’s emotions, social relationships,
finances, and medical choices.
People who receive a positive test result may feel anxious, depressed, or
angry. They may choose to undergo preventive measures, such as prophylactic
surgery, that have serious long-term implications and whose effectiveness
is uncertain.
People who receive a negative test result may experience “survivor
guilt,” caused by the knowledge that they likely do not have an increased
risk of developing a disease that affects one or more loved ones.
Because genetic testing can reveal information about more than one family
member, the emotions caused by test results can create tension within families.
Test results can also affect personal choices, such as marriage and childbearing.
Issues surrounding the privacy and confidentiality of genetic test results
are additional potential risks (see below).
- What can happen when genetic test results
are placed in medical records?
Clinical test results are normally included in a person’s medical
records. Consequently, individuals considering genetic testing must understand
that their results might not be kept private.
Because a person’s genetic information is considered health information,
it is covered by the Privacy Rule of the Health Information Portability and
Accountability Act (HIPAA) of 1996 (21). The Privacy Rule
requires that health care providers and others protect the privacy of health
information, sets boundaries on the use and release of health records, and
empowers individuals to control certain uses and disclosures of their health-related
information. Many states also have laws to protect the privacy and limit the
release of genetic and other health information.
In 2008, the Genetic Information Nondiscrimination Act (GINA) became Federal
law (see
Question 15). GINA prohibits discrimination based on genetic information
in relation to health insurance and employment, but the law does not cover
life insurance, disability insurance, and long-term care insurance. When applying
for these types of insurance, people may be asked to sign forms that give
an insurance company permission to access their medical records. The insurance
company may take genetic test results into account when making decisions about
coverage.
Some physicians keep genetic test results out of medical records. However,
even if such results are not included in a person’s medical records,
information about a person’s genetic profile can sometimes be gathered
from that person’s family medical history.
- What is genetic discrimination, and are
there laws to protect people from this type of discrimination?
Genetic discrimination occurs when people are treated differently by insurance
companies or employers because they have a gene mutation that increases their
risk of a disease, such as cancer. However, in 2008, GINA was enacted to protect
U.S. citizens against discrimination based on their genetic information in
relation to health insurance and employment (22, 23). The parts of the law
relating to health insurers will take effect between May 2009 and May 2010,
and those relating to employers will take effect by November 2009. The law
does not cover life insurance, disability insurance, and long-term care insurance.
In addition, the law does not cover members of the military.
Some of the protections under GINA with regard to health insurance include
the following:
- Premiums or contributions to a group health plan cannot be increased based
on the genetic information of an individual(s) enrolled in the plan.
- Insurers cannot require an individual or family member to undergo a genetic
test before enrollment in a group health plan.
- Insurers cannot request, require, or purchase genetic information about
an individual before the person’s enrollment in a group health plan
or in connection with that person’s enrollment in the plan.
- Health insurers cannot use genetic information as the only basis upon
which to claim a pre-existing condition is present and, therefore, to deny
coverage.
Some of the protections under GINA with regard to employment include the
following:
- Employers cannot refuse to hire and cannot fire individuals based on their
genetic information.
- Employers cannot discriminate against employees with regard to salary,
terms and conditions of employment, privileges, and opportunities for the
future because of their genetic information.
- Employers cannot request, require, or purchase genetic information about
an employee except under specific circumstances.
- Employers cannot disclose an employee's genetic information except under
specific circumstances.
Before GINA was passed, many states enacted laws against genetic discrimination.
The amount of protection provided by these laws varies widely from state to
state. GINA sets a minimum standard of protection that must be met by all
states. It does not weaken the protections provided by any state law.
- In general, what factors increase or decrease
the chance of developing breast cancer and/or ovarian cancer?
The following factors have been associated with increased or decreased risk
of developing breast and/or ovarian cancer in the general population. It is
not yet known exactly how these factors influence risk in people with BRCA1
or BRCA2 mutations. In addition, a significant portion of hereditary
breast cancers are not associated with BRCA1 or BRCA2 mutations
(8).
- Age—The risks of breast and ovarian cancer increase
with age. Most breast and ovarian cancers occur in women over the age of
50. Women with harmful BRCA1 or BRCA2 mutations often
develop breast or ovarian cancer before age 50.
- Family History—Women who have a first-degree relative
(mother, sister, or daughter) or other close relative with breast and/or
ovarian cancer may be at increased risk of developing these cancers. In
addition, women with relatives who have had colon cancer may be at increased
risk of developing ovarian cancer.
- Medical History—Women who have already had breast
cancer are at increased risk of developing breast cancer again, or of developing
ovarian cancer.
- Hormonal Influences—Estrogen is a hormone that
is naturally produced by the body and stimulates the normal growth of breast
tissue. It is thought that excess estrogen may contribute to breast cancer
risk because of its natural role in stimulating breast cell growth. Women
who had their first menstrual period before the age of 12 or experienced
menopause after age 55 have a slightly increased risk of breast cancer,
as do women who had their first child after age 30. Each of these factors
increases the amount of time a woman’s body is exposed to estrogen.
Removal of a woman’s ovaries, which are the main source of estrogen
production, reduces the risk of breast cancer. Breast-feeding also reduces
breast cancer risk and is thought to exert its effects through hormonal
mechanisms (24).
- Birth Control Pills (Oral Contraceptives)—Most
studies have shown a slight increase or no change in risk of breast cancer
among women taking birth control pills (24). In contrast,
numerous studies have shown that taking birth control pills decreases a
woman’s risk of developing ovarian cancer (25).
This protective benefit appears to increase with the duration of oral contraceptive
use and persists up to 25 years after discontinuing use. It also appears
that the use of birth control pills lowers the risk of ovarian cancer in
women who carry harmful BRCA1 or BRCA2 mutations (26).
- Hormone Replacement Therapy—Doctors may prescribe
hormone replacement therapy (HRT) to reduce the discomfort of certain symptoms
of menopause, such as hot flashes. However, the results of the Women’s
Health Initiative (WHI), a large clinical study conducted by the National
Heart, Lung, and Blood Institute, part of the National Institutes of Health
(NIH), showed that HRT with the hormones estrogen and progestin is associated
with harmful side effects, including an increased risk of breast cancer
and increased risks of heart attack, blood clots, and stroke. The WHI also
showed that HRT with estrogen alone was associated with increased risks
of blood clots and stroke, but the effect on breast cancer risk was uncertain
(27). In addition, the WHI showed an increase in ovarian
cancer risk among women who received estrogen and progestin HRT, but this
finding was not statistically significant (28). Because
of these potential harmful side effects, the FDA has recommended that HRT
be used only at the lowest doses for the shortest period of time needed
to achieve treatment goals.
No data have been reported to date regarding the effects of HRT on breast
cancer risk among women carrying harmful BRCA1 or BRCA2
mutations, and only limited data are available regarding HRT use and ovarian
cancer risk among such women. In one study, HRT use did not appear to
affect ovarian cancer risk among women with BRCA1 or BRCA2
mutations (29).
When considering HRT use, both the potential harms and benefits of this
type of treatment should be discussed carefully by a woman and her health
care provider.
- Obesity—Substantial evidence indicates that obesity
is associated with an increased risk of breast cancer, especially among
postmenopausal women who have not used HRT (24). Evidence
also suggests that obesity is associated with increased mortality (death)
from ovarian cancer (30).
- Physical Activity—Numerous studies have examined
the relationship between physical activity and breast cancer risk, and most
of these studies have shown that physical activity, especially strenuous
physical activity, is associated with reduced risk. This decrease in risk
appears to be more pronounced in premenopausal women and women with lower-than-normal
body weight (24).
- Alcohol—There is substantial evidence that alcohol
consumption is associated with increased breast cancer risk. However, it
is uncertain whether reducing alcohol consumption would decrease breast
cancer risk (24).
- Dietary Fat—Although early studies suggested a
possible association between a high-fat diet and increased breast cancer
risk, more recent studies have been inconclusive. In the WHI, a low-fat
diet did not help reduce breast cancer risk (31).
- Where can people get more information about
genetic testing for cancer risk?
A person who is considering genetic testing should speak with a professional
trained in genetics before deciding whether to be tested. These professionals
may include doctors, genetic counselors, and other health care workers trained
in genetics (such as nurses, psychologists, or social workers). For help finding
a health care professional trained in genetics, please visit NCI’s Cancer
Genetics Services Directory at http://www.cancer.gov/search/geneticsservices
on the Internet. Alternatively, please contact NCI’s Cancer Information
Service (CIS) (see below for contact information). The CIS can provide more
information about genetic testing and help in finding a health care professional
trained in genetics.
- What research is currently being done to
help individuals with harmful BRCA1 or BRCA2 mutations?
Research studies are being conducted to find newer and better ways of detecting,
treating, and preventing cancer in BRCA1 and BRCA2 mutation
carriers. Additional studies are focused on improving genetic counseling methods
and outcomes. Our knowledge in these areas is evolving rapidly.
Information about active clinical trials (research studies with people) for
individuals with BRCA1 or BRCA2 mutations is available on
NCI’s Web site. The following links will initiate searches of NCI’s
clinical trials database and retrieve lists of trials open to individuals
with BRCA1 or BRCA2 mutations.
In addition, NCI’s CIS can provide information about clinical trials
and help with clinical trial searches (see below for contact information).
We offer comprehensive research-based information for patients and their families, health professionals, cancer researchers, advocates, and the public.