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Date: September 28, 1995
For Release: 6 p.m. EDT
Contact: NIH/NCHGR (301) 402-0911 or
NIH/NCI (301) 496-6641
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.
"This exciting finding should allow us to move rapidly toward our goal of identifying high-risk women and helping them to prevent breast cancer before it strikes," said Donna Shalala, secretary of the U.S. Department of Health and Human Services.
With the publication of today's 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 today's 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 mutuation 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 already have 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.
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.
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 to 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.
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 abnormal features.
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 have a higher risk 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.
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.
It is estimated that from one in 300, to one in 800, women in the United States have an alteration in BRCA1.
A large number of different alterations has been identified in the BRCA1 gene. For the most part, each 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 Eastern 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.
NIH scientists found the 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.
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 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.
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.
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.
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.
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.
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.
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.
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.
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 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.
The Cancer Information Service (CIS), a program of the National Cancer Institute, provides a nationwide telephone service for cancer patients and their families, the public, and health care professionals. CIS information specialists have extensive training in providing up-to-date and understandable information about cancer and cancer research. They can answer questions in English and Spanish and can send free printed material. In addition, CIS offices serve specific geographic areas and have information about cancer-related services and resources in their region. The toll-free number of the CIS is 1-800-4-CANCER (1-800-422-6237).
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