Chicago Center for Jewish Genetics Disorders - Cancer Genetics

BRCA1 and BRCA2

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Overview of BRCA1 and BRCA2
How inheritances works for BRCA mutations
Genetic Testing for Breast and Ovarian Cancer
BRCA1
BRCA2
BRCA2 and Pancreatic Cancer
A Summary of BRCA Facts

Overview of BRCA1 and BRCA2

BRCA1 and BRCA2 are tumor suppressor genes, or genes which regulate cell growth and are needed to stop cancer from developing. These genes are involved in repairing damage to DNA but have many other functions that are still poorly understood. When tumor suppressor genes no longer function due to mutations, cancer may develop. Short for BReast CAncer 1 and 2, these two genes are associated with hereditary breast and ovarian cancer.

Individuals who are born with a mutated copy of BRCA1, for example, also carry a normally functioning copy since each parent transmits one copy of BRCA1 to the child to make a pair of genes. Loss of function of the normal copy of the gene is thought to be necessary before cancer will develop. It is believed that additional genetic mutations may be sustained through an interaction with the environment. A woman carrying a BRCA1 or BRCA2 mutation is therefore more likely, but not guaranteed, to develop breast and ovarian cancer than a woman in the general population. Because she has only one protective copy, she may take less time to develop cancer than a woman with two working copies, i.e. at a younger age.

Although there are many different mutations of the BRCA genes seen among different families, specific mutations are associated with certain ethnic backgrounds, including Ashkenazi Jewish ancestry. This has specific implications for the level of suspicion for cancer within Jewish families, the test performed, the costs, and the meaning of the results. (see Ashkenazi Jews and BRCA1 and BRCA2; Jewish Ancestry and Breast/Ovarian Cancer)

In general, hereditary causes may account for 5 to 10% of all breast and ovarian cancer cases, but the estimate is higher for younger-onset cancers. These estimates are much higher in Ashkenazi Jews. Of hereditary breast cancer families, 50 to 70% may found to be caused by mutations in the BRCA1 and BRCA2 genes. Women with mutations in either of these two genes are more likely to develop breast cancer but are not always destined to do so.

According to the body of cancer research, an individual with a BRCA1 or BRCA2 mutation has:

an 85% risk over her lifetime to develop breast cancer (often at an early age)
a 20 to 54% lifetime risk to develop ovarian cancer, generally higher for BRCA1 than BRCA2
a 40 to 60% lifetime risk of developing a second breast tumor
for a mutation carrier with breast cancer, no clear difference in survival compared to other women with breast cancer without a mutation.
for a mutation carrier with ovarian cancer, a better rate of survival compared to other women with ovarian cancer without a mutation.

How Inheritance Works for BRCA Mutations

Cancer is not inherited. It is the predisposition to cancer that is inherited, and in the case of the BRCA genes, this predisposition is inherited in an autosomal dominant manner (i.e., anyone who is a child or sibling of an individual who carries a BRCA mutation has a 50% chance of also inheriting the mutation). The inheritance pattern in a family with a BRCA1 or BRCA2 mutation is called “autosomal dominant”. With this form of inheritance, an individual with a BRCA1 or BRCA2 mutation has a 50% chance of passing on the mutation to each child.

Here’s how it works. The job of tumor suppressors, such as BRCA1 and BRCA2, is to control cell growth. Every individual has two copies of all the genes in their body, and BOTH copies of the gene (BRCA1 or BRCA2) need to be mutated before cancer develops. This is because a single copy of both genes is enough to control cell growth. A way to think of this is to compare a tumor suppressor gene to brakes on an automobile. If the rear set of brakes is not working, the car can still be stopped by the front brakes. However, if both the rear and the front set of brakes are not working correctly, the car cannot be controlled. This is how tumor suppressor genes work. If one copy of the gene is functional, cell growth is still controllable. However, when both copies of the gene no longer work, the cell can grow out of control. Therefore, in an individual born with a BRCA1 or BRCA2 mutation (also called a germline mutation), the lifetime risk to develop cancer is much higher than in an individual born with two working copies of the gene.

Genetic Testing for Breast and Ovarian Cancer

The probability of carrying a BRCA1 or BRCA2 mutation depends upon the specific features in one’s personal or family history of breast or ovarian cancer. A mutation is more likely to be responsible for the breast or ovarian cancer occurring in a family if a family history includes:

Breast cancer diagnosed in anyone in the family before the age of 50 years
One or more first-degree relatives affected with breast or ovarian cancer
Multiple generations affected by cancer on the same side of the family
Bilateral breast cancer or multiple primary tumors in the same breast
Ovarian cancer at any age
Male breast cancer
The occurrence of both breast and ovarian cancer in the same person in a family
Ashkenazi Jewish ancestry and a history of breast cancer or ovarian cancer in the family
Additional cancers in the family, such as pancreatic cancer

For BRCA1 or BRCA2 mutations, testing is ideally first given to an individual affected by cancer. This is done prior to testing any unaffected family members. This is necessary to determine if a detectable BRCA1 or BRCA2 mutation is responsible for the breast and/or ovarian cancer within a family. After a cancer-predisposing mutation has been identified in an affected family member, BRCA1 or BRCA2 mutational analysis is much more informative for unaffected relatives. If an unaffected family member is then tested for a known mutation,in the family, the results are either:

Positive for the presence of a mutation known to occur in the family. This individual is at an increased risk to develop breast and ovarian cancer.
OR
Negative for the presence of a mutation known to occur in the family. This individual is NOT at increased risk. However, her risk does NOT go to zero; this individual still has the general population risk to develop breast and ovarian cancer (1 in 8 or 12%).

Also possible, is that a cancer-predisposing mutation in the BRCA1 or BRCA2 gene will not be identified in an affected individual. A negative result may mean that either a mutation is present that was not detected in the gene due to testing limitations, or this individual may have a mutation in a different gene that predisposes to breast and/or ovarian cancer. If unaffected family members were then tested for a BRCA1 or BRCA2 mutation, a negative result would not clarify their risk of developing breast and/or ovarian cancer.

It is also more costly to test an unaffected individual first, unless the results happen to be positive. A negative result should be followed up with testing an affected relative in the family. If positive, the unaffected has a true negative result. If negative, genetic testing has not clarified cancer risks in the family (and now two gene tests have been done instead of one).

There are also many emotional and ethical aspects associated with genetic testing. For a more in-depth discussion of this topic, see Emotional Aspects of Testing.

BRCA1

The lifetime risk to develop breast cancer is 1 in 8 or 12%. The risk to develop breast cancer in an individual with a BRCA1 or BRCA2 mutation begins in one’s 20s and as the lifetime risk is about 85% by the age of 80.

Ovarian cancer is generally not seen in women under the age of 40 or women but can occur. A wide variation of risk 20-54% by age 80 has been reported; the higher risks are supported by recent data. The risk in the general population is about 1 to 2%.

Male breast cancer has been observed in BRCA1 mutation carriers with a lifetime risk likely below 5%. The risk of prostate cancer may be up to be 3 times greater in men who have a BRCA1 mutation than in the general population. The cumulative risk has been estimated at 6 to 8% by age 70 years compared to 2% in the general population.

Previous data have suggested that men and women with a BRCA1 mutation are at higher risk to develop colon cancer than the general population risk of 2%. However, two recent articles provide definitive data that no such correlation exists and therefore, an individual with a BRCA1 mutation is given the same recommendations as individuals at average population risk.

Despite the fact that most BRCA1 mutations known to cause cancer are often unique to a family, different ethnic populations have shown specific genetic BRCA1 mutations. For example, the Dutch commonly have two large deletions. There are two mutations known to occur at a high frequency in the Ashkenazi Jewish population. This is discussed more extensively in Ashkenazi Jews and BRCA1 and BRCA2.

BRCA2

BRCA2 has a similar clinical profile as BRCA1. BRCA2 is a tumor suppressor gene located on chromosome 13, locus 13q12.3. Like BRCA1, BRCA2 limits the growth of cells. The risk to develop breast cancer in an individual with a BRCA2 mutation is not significantly different than that for individuals with a BRCA1 mutation. This risk begins in one’s 30s and is as high as 85% by age 80.

Ovarian cancer risk in women with a BRCA2 mutation is 23% by the age of 80, versus 1-2% in the general population. This is lower than the risk for women with a BRCA1 mutation. Individuals with BRCA2 mutations face an increased risk for pancreatic cancer, in the range of 7% over a lifetime .

In men with BRCA2 mutations, there is an increased risk for breast cancer. The risk for male mutation carriers is 5 to 6 % over a lifetime versus 0.05% seen in the general population. Looking at this from a different perspective, a BRCA2 mutation was found in 4 to 14% of all cases of male breast cancer. There is also an increased risk for prostate cancer of 6 to 14% versus 2% seen in the general population.

Despite the fact that most cancer causing BRCA2 mutations are unique to a family, different ethnic groups have been shown to have a high incidence of specific BRCA2 mutations. For example, the 999del5 mutation occurs in 0.6% of the Icelandic population. There is one mutation known to occur more commonly in the Ashkenazi Jewish population, called 6174delT. This is discussed more extensively in Ashkenazi Jews and BRCA1 and BRCA2. For example, seven percent of patients with pancreatic cancer who are Ashkenazi Jewish carry a BRCA2 mutation.

BRCA2 and Pancreatic cancer

Individuals with a BRCA2 mutation are also at risk to develop pancreatic cancer. It is known that individuals of Ashkenazi Jewish ancestry are at higher risk than other religious groups to develop pancreatic cancer, although it is unclear why. The lifetime risk to develop pancreatic cancer is 1%, but in a Jewish individual with a BRCA2 mutation, that risk may be as high as 7-10%. In one study of European families with at least two first degree relatives with pancreatic cancer, 19% were found to carry a BRCA2 mutation.

Due to the complexity of this information and possible personal implications, any individual interested in pursuing cancer genetic testing should speak with a qualified genetic counselor who specializes in inherited cancer susceptibility. To find a genetics professional in the Chicago area, please visit the Genetic Counseling and Screening section of the website at http://www.jewishgeneticscenter.org/genetic/counselors/. To find a genetics center outside of the Chicagoland area, please visit www.nsgc.org, www.geneclinics.org (clinic directory) or www.acmg.net. For more information regarding recommended guidelines for genetic testing, please refer to the ASCO guidelines.

Scientists at Johns Hopkins are actively working to identify genes and are developing therapies that specifically target cancer cells with mutations common in pancreatic cancers in the Ashkenazi Jewish population. If you are of Ashkenazi Jewish ancestry and have pancreatic cancer or a family history of pancreatic cancer, please consider participating in one of our research studies. To learn more about how you can help please contact Emily Palmisano (410-955-3502 or epalmis1@jhmi.edu).

A Summary of BRCA1 and BRCA2 Facts

Certain ethnic groups are at increased risk for having BRCA1 and BRCA2 mutations; three particular mutations are more common among Ashkenazi Jews.
Women with mutations in BRCA1 or BRCA2 are more likely to develop breast or ovarian cancer but are not guaranteed to do so.
A BRCA1 or BRCA2 mutation is more likely to be found in an individual with a family history of particular cancers.
Women with BRCA1 or BRCA2 mutations are more likely to get cancer at a younger age than the general population.
Men can also have BRCA1 or BRCA2 mutations, which puts them at an increased risk for prostate, breast, and some other cancers.
A BRCA1 or BRCA2 mutation can also be passed down through the father so it is important to consider both sides of the family history.
The decision to get tested can be very complicated. Talk to your doctor or a genetic counselor if you are interested in testing.

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This page last updated on March 17, 2006.