Cancer Risk in Ashkenazi Jews

by National Cancer Institute

In 1995, scientists from the National Institutes of Health (NIH) discovered that a particular alteration in the breast cancer gene called BRCA1 was present in 1 percent of the general Jewish population. The researchers did a followup study in 1996 to estimate the cancer risk associated with this alteration as well as two other alterations subsequently reported to be present in the Ashkenazi Jewish population. This study was a cooperative effort between the Washington, D.C., Jewish community and scientists from the National Cancer Institute (NCI) and the National Human Genome Research Institute. The following questions and answers serve as background information on the followup study published in the May 15, 1997, issue of The New England Journal of Medicine.

1. What was the purpose of the study?

The primary purpose of the study was to estimate the risk of cancer associated with three specific alterations in the breast cancer genes BRCA1 and BRCA2. The study was conducted in the Washington, D.C., Ashkenazi Jewish population (Jews from eastern or central Europe). Two of the alterations tested were in the BRCA1 gene (185delAG and 5382insC), and one was in the BRCA2 gene (6174delT).

The researchers tested the DNA in blood provided by a finger-prick to see which of the 5,318 volunteers had an alteration. Then, using the family cancer histories reported by the volunteers, the scientists estimated the cancer risk by comparing the histories of cancer in the relatives of the volunteers with the alteration to the histories of cancer in the relatives of the volunteers without the alteration.

2. What was unique about the study?

This was the first study to test DNA from volunteers who are not selected for testing because they are part of cancer-prone families and to estimate the cancer risk associated with each alteration. (For years, researchers have studied families with breast cancer throughout several generations to help identify the altered genes passed on from one generation to the next.)

This was the first community-based study in which men and women with varying degrees of family cancer history participated. In fact, 76 percent of the volunteers had no personal or close family history of breast or ovarian cancer. About 8 percent of the women (302 of 3,742) were breast or ovarian cancer survivors.

The scientists who conducted this study had discovered in previous research that one of the alterations (185delAG) in BRCA1 was present in an unusually high proportion of anonymous stored blood samples from the general Jewish population. Even though the frequencies they found were unexpectedly high (see references in question 4), it was impossible to estimate the cancer risk associated with the alterations because the cancer history of the blood donors was not known.

The study described here was designed both to test for the frequency of the alterations and to find out if alteration carriers from the general population were at greater risk for cancer than those without an alteration.

3. What is known about the BRCA1 and BRCA2 genes?

Because family history is the strongest single predictor of a woman's chance of developing breast cancer, researchers turned to cancer-prone families--those with a high incidence of cancer in several generations--to find specific inherited gene alterations that are passed on from one generation to the next. After a long search, two genes were found that are altered in many families with hereditary breast cancer. The first, BRCA1 (for BReast CAncer gene), was discovered in 1994, and the second, BRCA2, in 1995. (Alterations in other genes, including p53 and Rb, are also associated with breast cancer susceptibility. Scientists continue to search for additional genes involved in the development of breast cancer.)

Within families with cancer in multiple generations, it had been estimated previously that a woman with an alteration in the BRCA1 gene has about an 85 percent chance of developing breast cancer and a 44 percent chance of developing ovarian cancer by age 70. Prior research in these high-risk families had reported that women with BRCA2 alterations have a lower risk of developing both breast and ovarian cancer than women with BRCA1 alterations. Previous studies had reported an increased risk of colon and prostate cancer among alteration carriers in these same families.

Most alterations result in a shortened protein product that scientists believe prevents the protein from carrying out its normal function in the cell. The precise biological roles of BRCA1 and BRCA2 are not known.

Once the genes were isolated, it was possible to analyze the specific alterations inherited in each cancer-prone family. Today several hundred different alterations scattered throughout BRCA1 have been identified. In general, most families have a unique alteration. A similar pattern is emerging for BRCA2 alterations seen in cancer-prone families; a large number of distinct, family-specific alterations are scattered throughout the gene.

The initial impetus for this study was the observation in late 1994 that three high-risk Ashkenazi families studied at the NIH carried an identical alteration in BRCA1 (185delAG). These families were not known to be related. This observation led to the study which found that 1 percent of the Jewish population has this alteration. This was the first alteration associated with a particular ethnic group. A few other alterations that occur frequently in other ethnic groups (Icelandic, Norwegian, and Dutch) have been found since then.

4. Why were these particular alterations chosen to be tested?

Of the more than 100 alterations identified in each gene (BRCA1 and BRCA2) in families with hereditary breast cancer, a few are found in subgroups of the general population. In particular, three alterations were initially identified in Ashkenazi families with hereditary breast cancer and later were found in an unusually high percentage of the general Jewish population. The estimated frequencies of the three alterations in the general Ashkenazi population, derived from previous studies, are listed below:

Gene	Alteration	Frequency in Ashkenazi Jews
BRCA1	185delAG	1.0 percent
BRCA2	6174delT	1.4 percent

Nature Genetics 1995; 11:198-200 and Nature Genetics 1996; 14:185-187, 188-190.

In comparison, the percentage of people in the general U.S. population that have any mutation in BRCA1 has been estimated to be between 0.1 percent and 0.6 percent.

About the Author

www.nci.nih.gov
The National Cancer Institute's research programs are extensive and contain many innovative initiatives. I invite you to explore our Web site to find out more about the exciting work being conducted here at NCI and by NCI-supported scientists throughout the country.