Specific BrCa1 gene mutation identified in
Ashkenazi jewish population
Anthony C. Cahan, M.D., and George H. Bock, M.D.
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3.Questions and Answers
Scientists Report New Lead in Genetics of Breast Cancer
Nearly 1 percent of over 850 DNA samples from Eastern European Jews contained a specific gene mutation that
may predispose them to breast and ovarian cancer, according to study results published today in Nature Genetics.
This finding offers the first evidence from a large study that an alteration in the gene, called breast cancer
1 (BRCA1), is present at measurable levels not only in families at high risk for the disease, but in a specific
group of the general population. Using this new information, researchers now can design studies that will help
them better determine the role of BRCA1 in cancer.
With the publication of these results, the National Institutes of Health (NIH) also announced it plans to launch
a series of clinical studies to evaluate cancer risk in Eastern European, or Ashkenazi, Jews bearing the mutation.
The results of these studies will help determine whether BRCA1 testing should be offered to the nation's six million
Ashkenazi Jews as a part of their health care.
But based on these results alone, the authors stressed their data were too preliminary to recommend immediate
BRCA1 testing. "While the finding raises the possibility of testing, it does not provide any data on precise
cancer risk," said Dr. Jeff Struewing, the lead author of the paper and a scientist with the National Cancer
Institute (NCI) and the National Center for Human Genome Research (NCHGR). "Until more detailed information
is available, it is premature to recommend that Ashkenazi women seek BRCA1 testing."
Isolated in September 1994, BRCA1 is the first major gene to be found that, when one of its two copies is inherited
in an altered form, predisposes individuals to breast and/or ovarian cancer.
Scientists estimate women from BRCA1 families who inherit a mutation in the gene have up to a 90 percent lifetime
chance of developing breast cancer. In many cases, breast cancer arises before age 50. The risk of ovarian cancer
is suspected to be as high as 84 percent in some families.
Because their data are based on families with strong histories of cancer, scientists have previously had no
way of designing studies to determine the risk of BRCA1-linked cancer in women without a strong family history
of the disease.
Within the last year, two research teams independently observed a specific, two-base deletion, called 185delAG,
in the BRCA1 genes of 10 families with histories of breast and ovarian cancer. The scientists also noticed each
of these families was of Ashkenazi Jewish heritage. A base, like letters to the alphabet, is the chemical subunit
that comprises DNA.
Following up on this report and producing today's results, three research groups in the United States and Israel
jointly tested 858 DNA samples from unrelated Ashkenazi Jews. These individuals were randomly selected for testing
regardless of the presence or absence of a family history of cancer.
The tests showed eight of the samples contained one copy of the BRCA1 gene that had the 185delAG deletion. This
translates to 0.9 percent, a carrier rate for this single mutation in the sample group that is at least three times
higher than the estimated carrier rate for all BRCA1 mutations combined in the general U.S. population.
The deletion would likely lead to a shortened and non-functional protein product. Based on the current U.S.
census and epidemiological data on BRCA1-linked cancer, the researchers suspect the deletion might possibly account
for as much as 16 percent of breast and 39 percent of ovarian cancers in Ashkenazi Jewish women age 50 and under.
In the general U.S. population, inherited BRCA1 alterations are estimated to contribute to 4 percent of breast
and 12 percent of ovarian cancers.
"Our results will allow us to test the validity of these predictions in those with an altered BRCA1 gene,"
said Dr. Lawrence Brody, the senior author and scientist in the intramural research program at NCHGR.
Given the potential health care implications of the finding, NCI and NCHGR have already begun to mobilize for
clinical studies with Ashkenazi Jews in the United States. In the first proposed study, researchers will test several
thousand Ashkenazi Jews for the 185delAG alteration and gather information on their medical and family history.
"We expect to have the first protocol finalized in the coming weeks," said Dr. Richard Klausner, NCI
director. "Once completed, these studies should tell us a great deal more about the family histories of those
with the deletion and will help define their risk of cancer. Answering these questions is the first step. Then
we must begin to address the effectiveness of genetic counseling and screening in reducing morbidity and mortality
from any cancers that might be associated with the mutation."
But according to Dr. Francis Collins, NCHGR director and one of the authors of today's paper, finding the 185delAG
deletion also highlights another emerging issue in medicine.
"Population-based studies on the genetic level are becoming a real possibility and may help pinpoint which
groups of people have a inherited susceptibility to certain diseases," said Dr. Collins. "But as our
knowledge of human genetics grows, so too does the possibility of genetic discrimination in employment and health
insurance. This finding only underscores society's need to address these critical issues."
The National Center for Human Genome Research and the National Cancer Institute are components of the National
Institutes of Health, which is part of the U.S. Department of Health and Human Services.
This document was prepared by:
The National Center for Human Genome Research, NIH
The National Cancer Institute, NIH
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The 185delAG Alteration in BRCA1: What does this mean for Jewish women?
What is BRCA1?
Genes contain the hereditary information that is passed down from parent to child. They serve as the blueprint
for many features. Everyone has two copies of a gene called BRCA1 in the cells of their body, one inherited from
their mother and one from their father. In most people, both BRCA1 genes function normally. But in some individuals,
one copy carries a misspelling. This change, or alteration, can occur at hundreds of different sites along the
BRCA1 gene. Some of these changes make a person more at risk for developing breast or ovarian cancer, and may possibly
be associated with cancers of the colon and prostate.
In a recent research study, one particular alteration in BRCA1, known as 185delAG, was found to occur more frequently
in a group of Jews of Eastern European descent (Ashkenazi Jews) than among other ethnic groups in the study. Approximately
1 percent of Ashkenazi individuals were found to carry this alteration in this preliminary study. The National
Cancer Institute and the National Center for Human Genome Research will soon begin another research study of the
Ashkenazi Jewish population to determine exactly how common this alteration is and how often this alteration is
related to the incidence of breast cancer and ovarian cancer.
Research on BRCA1 alterations will eventually help scientists better understand what goes wrong inside a cell
when it becomes cancerous. This research is expected to lead to earlier methods of detection, more effective treatments,
and more successful preventive strategies in the future. In the meantime, because of the uncertainties surrounding
the interpretation of the test results, testing is being offered in research protocols. Anyone wishing to learn
more about this research or who is interested in participating in this research, may contact the number listed
below for further information.
What we know and don't know about BRCA1 alterations:
Known: Most people who develop breast cancer, including those in the Jewish population, have normal BRCA1
genes. In fact, only about 5-10 percent of all breast cancer cases appear to be inherited and not all of these
are related to BRCA1.
Unknown: Although certain to be fairly low, the exact percentage of inherited breast and ovarian cancers
in the Jewish population is not known.
Known: Women with a strong family history of breast and/or ovarian cancer who have inherited an alteration
in BRCA1 have a substantial risk of developing breast and/or ovarian cancer. This often occurs at an unusually
early age, for instance, before menopause.
Unknown: The cancer risks for an individual without a strong family history who is found to carry the
185delAG alteration is not known. There are other factors such as lifestyle, hormonal factors, environmental influences,
and other inherited traits that affect cancer risks. As testing for alterations in the BRCA1 gene becomes available
to researchers, the interaction of these factors can be studied.
Known: Not all women who carry the BRCA1 alteration will develop breast or ovarian cancer.
Unknown: The alteration is not the single cause of disease, only a contributing factor. There must be
other factors, yet unknown, that affect the development of cancer in addition to having an altered BRCA1 gene.
Therefore, people who carry the altered gene are said to have a susceptibility to breast and ovarian cancer.
Known: There is a risk that genetic information can be used to discriminate against those individuals
found to be susceptible to disease. Researchers must keep the data they collect private and confidential. However,
if results of the tests are given to the individual, insurance companies, employers, child adoption agencies and
others may require that the person share the results of this test with them.
Unknown: The extent to which discrimination based on genetic information will become widespread is not
clear. There are only a few states in which legislation has been enacted to prevent health insurance discrimination
following genetic testing. Efforts are underway by consumer groups to limit discriminatory practices based on genetic
Known: Not everyone will want to be tested for genetic susceptibility to disease. Whether or not to be
tested is a personal choice that should be made only after thoughtful consideration of the benefits and risks associated
with testing. Each person should be informed of the known risks and benefits of genetic testing and have a chance
to discuss these issues with a knowledgeable health care provider before deciding whether or not to be tested.
Unknown: Much is still unknown about the psychological impact of genetic testing on individuals and families,
as well as other issues that affect how one evaluates risks and benefits. All the risks and benefits of genetic
testing have not yet been determined.
An informed decision about genetic testing is often very difficult to make because all the risks and benefits
have not yet been determined and will be constantly changing with time. Important considerations, such as the psychological
impact of genetic testing, may vary greatly among individuals and families.
Known: If a woman tests negative for an alteration in BRCA1, she may still get breast cancer. On average,
a woman has a one in eight lifetime risk of developing breast cancer.
Unknown: All the genes that may increase a woman's risk of breast and ovarian cancer have not been identified
and, therefore, cannot be tested for.
Known: Women who carry an alternation in BRCA1 should be monitored closely for breast and ovarian cancer.
Unknown: There is much research that needs to be done to help women who carry an altered BRCA1 gene make
choices about their future medical care. Women should be aware that many things, such as, what age to begin mammography,
what diagnostic test to have done for early diagnosis of ovarian cancer and the effectiveness of prophylactic mastectomies
(removal of a woman's healthy breast to reduce her risk of breast cancer) or ovariectomy (removal of the ovaries)
have not been studied in people who have an alteration in the BRCA1 gene. While awaiting more scientific answers,
women are encouraged to learn as much as they can about their options for medical care and to be actively involved
in their health care decisions.
Anyone wishing more information about medical management options or research studies designed to learn more
about medical management should contact the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
This document was prepared by:
The National Center for Human Genome Research, NIH The National Cancer Institute, NIH
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Breast Cancer and the BRCA1 Gene: Questions and Answers
Scientists report in Nature Genetics (Oct. 1, 1995) that they have found a specific alteration of the BRCA1
gene in approximately one percent of a group of Askenazi Jews. Additional research will be needed to see if this
alteration increases breast cancer risk in those who have it.
1. What is breast cancer?
Breast cancer is a group of related diseases in which cells within the breast become abnormal and divide without
control or order, invading and damaging nearby tissues and organs. When cancer cells break away from the original
tumor and enter the bloodstream or lymphatic system, breast cancer may spread and form secondary tumors (metastases)
in other parts of the body. The most common types of breast cancer arise in the lining of the ducts or in the lobules
of the breast.
2. What is the risk of developing breast cancer?
In the United States, a woman's lifetime risk of developing breast cancer is about 12 percent. An average woman's
chances of getting breast cancer is about one in 200 by age 40, one in 50 by age 50, and one in 25 by age 60. In
some families, where breast cancer occurs in an inherited pattern, the risk is higher. About 5-10 percent of women
with breast cancer have a hereditary form of the disease. These women usually have a higher risk of developing
breast cancer at a younger age (before menopause), and they often have multiple family members with the disease.
3. What are the risk factors for breast cancer?
By studying large numbers of women all over the world, researchers have found certain risk factors that increase
a woman's chance of developing breast cancer. Many women who get breast cancer have none of the known risk factors,
other than the risk that comes with growing older. And, studies show that most women with known risk factors do
not get breast cancer. Some of the known risk factors are:
Age. The risk of breast cancer increases as a woman gets older. Most breast cancers occur in women over
the age of 50; the risk is especially high for women over 60. This disease is uncommon in women under the age of
35, except in some families with the hereditary form of the disease.
Family history. The risk of getting breast cancer increases for a woman whose mother, sister, or daughter
has had the disease. A woman's risk increases more if her relative's breast cancer developed before menopause or
if it affected both breasts.
Personal history. The risk of breast cancer is greater than average in women who have had a previous
breast cancer; carcinoma in situ, an abnormality of breast cells that is not considered cancer but has the potential
to become an invasive cancer; or atypical hyperplasia, a noncancerous condition in which breast tissue has certain
Other risk factors for breast cancer include starting to menstruate at an early age (before 12) or having
a late menopause (after 55). The risk is also greater for women who had their first child after the age of 30 and
for those who never had children. Tall women have a slightly higher risk for premenopausal breast cancer, and obese
women for breast cancer over age 50. These factors may all be related to a woman's natural hormones.
Alcohol consumption and use of hormonal medications have been associated with increased risk. Scientists are
also studying whether diet, exercise, pesticides, electromagnetic fields, engine exhausts, contaminants in food
and water, and abortion and miscarriage may be related to breast cancer risk. Some studies suggest that eating
plenty of vegetables, fruits, and whole grains or other lifestyle modifications may reduce risk.
4. What is BRCA1?
BRCA1 is the name of a gene located on chromosome 17 that is altered in certain families with an inherited susceptibility
to breast cancer. In these families, women who inherit the altered gene have up to a 90 percent lifetime risk of
developing breast cancer. Researchers estimate that more than half of these women will be diagnosed with breast
cancer by age 50, and more than 85 percent will have a diagnosis of breast cancer by age 70. Cancer risk may depend
in part on the specific type and location of the alteration within the gene.
Some families with BRCA1 alterations have a tendency to develop both breast and ovarian cancers.
Women who inherit BRCA1 alterations tend to develop breast cancer at younger ages than women in the general
population. However, the disease may also occur at older ages in women with BRCA1 alterations, and some may never
get the disease. Men who inherit the altered gene do not appear to have an increased risk of breast cancer, but
can pass the altered gene to their children. There is also some evidence for a slight increase in risk of prostate
cancer among carriers of a BRCA1 alteration.
5. How many women have an altered BRCA1 gene?
It is estimated that from one in 300, to one in 800, women in the United States have an alteration in BRCA1.
6. Is there a pattern of inheritance for specific alterations in the BRCA1 gene?
A large number of different alterations has been identified in the BRCA1 gene. For the most part, a BRCA1 family
carries a particular, characteristic alteration. Recently, Canadian and U.S. scientists identified one particular
alteration in several families with multiple cases of breast, or breast and ovarian cancers. These high-risk families
were all from an Ashkenazi Jewish background, with roots in Europe. So far, information from 10 such families is
published in the scientific literature.
This particular alteration is named 185delAG. Two adjacent pairs of DNA subunits (nucleotides) are missing in
the altered gene. This alteration, which is like taking two letters out of one word in a long book chapter, causes
the cell to shorten its translation of the gene's usual instructions for making a protein. At the present time,
scientists do not know the function of the protein encoded by the normal gene.
7. What is the finding of the NIH study which appears in the Oct. 1, 1995 Nature Genetics?
NIH scientists found the BRCA1-185delAG alteration in blood samples from 1 percent (8 of 858) Ashkenazi Jews
whose family or personal cancer histories are not known. This rate of alteration in the BRCA1 gene is at least
three times higher than all BRCA1 alterations combined in the general population. They did not find the alteration
in 815 other blood samples from individuals not selected for ethnic origin.
8. What are the implications of the study?
The findings suggest that the 185delAG alteration in BRCA1 may be more common in the Ashkenazi Jewish population
than in other groups. However, from these results, scientists still do not know whether, and to what degree, having
the altered gene increases a woman's risk of developing breast or ovarian cancers. To answer that question, they
must study in detail the family history of cancer in Jewish women who carry the 185delAG alteration.
NIH scientists are working closely with Jewish community leaders to conduct a follow-up study of a sample of
3,000 to 5,000 people from the Ashkenazi Jewish population in the Washington, D.C. area. Jewish community leaders
have offered to help develop educational materials, contact members of the Jewish community, field the study, and
inform participants and the Jewish community about the findings. Individual results will not be revealed to participants
in this phase of the study, but genetic testing and counseling may be available once more is known about the effects
of this particular alteration in the BRCA1 gene.
The National Cancer Institute (NCI) also is planning a study on Long Island, New York, where there is a sizeable
Ashkenazi population, and other scientists in the United States have also expressed interest in conducting studies
of the BRCA1-185delAG alteration.
The results of these new surveys may have implications for physician monitoring of certain women for breast
cancer occurrence, as well as for other research on breast and ovarian cancers.
9. Do Ashkenazi Jews have a higher incidence of breast cancer than the general population?
At this time, scientists cannot answer this question definitively. More than 90 percent of the estimated six
million U.S. Jews are Ashkenazi, according to Jewish sources. Although some epidemiologists have suggested that
Jewish women in the United States have higher breast cancer rates, most studies have not looked at how much of
the breast cancer risk can be explained by known risk factors, and most breast cancer studies have not recorded
the religion of participants. In addition, the U.S. Census Bureau does not record the religious background of individuals
in the U.S. population.
10. Is it possible to test a person's DNA for the alterations in the BRCA1 gene associated with breast cancer
Checking for possible alterations requires a thorough and complex examination of the entire gene. Experts on
BRCA1 examine blood samples from patients and family members. Such tests at present should be done only in research
laboratories because the tests are labor-intensive and expensive. Interpretation of the results is technically
difficult, resulting in an unknown rate of false-negative findings (that is, the test does not show an alteration,
when one may be present).
Only a relatively few laboratories are able to perform the test reliably, and resources for such testing are
extremely limited. Because of the uncertainties surrounding interpretation of the test results, a woman should
accept testing only in a research setting.
Before testing, participants in NIH-funded research studies receive counseling to help them decide whether to
go ahead with the process. Having the results before scientists themselves fully understand the role of the gene
in breast cancer development can have a potentially adverse impact on individuals and their family members.
11. How will scientists test for the 185delAG alteration?
A blood test will tell scientists whether an individual's DNA has the 185delAG alteration. At present, testing
being done for research purposes offers individuals education and counseling in addition to the blood test. Testing
for this specific alteration means that scientists will not have to sift through the entire gene for alterations.
12. Why is counseling necessary?
Genetic testing for BRCA1 alterations is different from traditional medical tests. Scientists may need blood
samples from not just one, but several family members. Because the issues surrounding gene testing for cancer predisposition
are complex and far-reaching, not just for the individual but for the entire family, participants who would like
to know their test results should consider discussing BRCA1 testing with a genetics counselor and/or other health
professional who is experienced in counseling on genetics issues. One issue is genetic discrimination, an important
consideration for health and life insurance, employment, and child adoption. Another issue is personal well being.
While knowledge can be empowering, it also can be overwhelming and anxiety-provoking.
Although research is underway to evaluate the possible social and psychological implications of genetic testing,
at the present time researchers do not know what monitoring or medical followup to recommend to individuals who
have an alteration in the BRCA1 gene, and individuals are advised to seek help in understanding the personal and
social ramifications of BRCA1 testing. The NIH will be sponsoring studies to examine various counseling and medical
surveillance options for carriers of an altered BRCA1 gene.
13. Have other genes besides BRCA1 been implicated in breast cancer?
Yes, there are several, and diet and other environmental exposures also may be important. About one-half of
inherited breast cancers are associated with alterations in the BRCA1 gene. Another gene, BRCA2, recently was mapped
to chromosome 13, but has not yet been isolated. An increased risk of breast cancer has also been observed in families
with other inherited diseases, such as ataxia telangiectasia; and the Li-Fraumeni syndrome, characterized by multiple
family members with soft tissue sarcoma, breast cancer, and leukemia.
A number of other genes are associated with breast cancer. The changes in these genes probably occurred during
a person's lifetime, and are not inherited like the alterations associated with hereditary breast cancer. Some
of these genes have been implicated in causing breast cancer, while others are believed to be involved in disease
invasion and metastasis. These include the genes named p53, AT, and a group known as GADD repair genes. Others
being studied include the RB suppressor gene, the HER-2/neu oncogene, and genes that help regulate the cell cycle.
14. Are tests for alterations in these genes available to the public?
Generally, no. At the present time, several gene tests are being offered in research studies as a way to help
track patients' progress during cancer treatment. No gene tests are currently available for determining risk of
breast cancer in the general population.
15. What about other groups, such as African Americans, who also may have higher breast cancer incidence
at younger ages than other American women?
Both NCI and the National Center for Human Genome Research (NCHGR) are conducting research to examine whether
alterations in BRCA1 are associated with breast cancer risk in African American families having multiple individuals
with breast cancer.
16. Where can a woman go to be counseled and/or tested if she is concerned about a possible inherited risk
for breast cancer?
At the present time, only a limited number of centers are able to offer counseling and testing. Most family
physicians will not be able to offer testing at present. A woman with a mother or sister with breast cancer who
is interested in being tested will need to ask his/her physician to contact a testing center for more information.
Contact the National Cancer Institute's Cancer Information Service at 1-800-4-CANCER for information about breast
cancer and for sources of information about counseling and testing options.
This document was prepared by:
The National Center for Human Genome Research, NIH
The National Cancer Institute, NIH