The results of the research, which involved 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, are published in the May 15 issue of The New England Journal of Medicine.*
"For several years we have known that having these alterations increases the cancer risk in families with a lot of cancer," said NCI Director Richard D. Klausner, M.D. "Now we know that even outside high-risk families, people with these alterations have an increased chance of getting breast, ovarian, or prostate cancer, but not as great a chance as previously thought."
Until now, estimates of the cancer risk associated with BRCA1 or BRCA2 mutations were derived mainly from families with a high incidence of breast and ovarian cancer throughout several generations. These studies estimated that a woman with an alteration had a 76 percent to 87 percent chance of developing breast cancer by the age of 70; for ovarian cancer, the risk ranged from 11 percent to 84 percent.
In contrast, the current work, in which three-quarters of the volunteers had neither a personal nor a close family history of breast or ovarian cancer, shows that, on average, women carrying one of the three alterations have a 56 percent chance of getting breast cancer by the age of 70 (compared with a 13 percent chance for women without the alterations) and a 16 percent chance of getting ovarian cancer (compared with 1.6 percent for non-carriers).
"The risk of breast cancer is not uniformly high for all women who carry a BRCA1 or BRCA2 mutation," said Jeffery P. Struewing, M.D., the principal investigator from NCI's Genetic Epidemiology Branch.
"We don't know which carriers are at highest risk, because we don't know what factors modify cancer risk. There could be other genes or environmental factors involved," continued Struewing.
Besides estimating the risk for breast and ovarian cancers, the research provides convincing evidence that prostate cancer is linked to alterations in these genes. The scientists estimated that men with one of the alterations have a 16 percent chance of getting prostate cancer by age 70 compared with 3.8 percent for non-carriers.
The new study involved more than 5,000 Ashkenazi Jews (those with origins in central and eastern Europe, comprising about 90 percent of the 6 million Jews in the United States) from the Washington, D.C. metropolitan area. The volunteers included both men and women between ages 21 and 94. Seventy-six percent of the participants had neither a personal nor a close family history of breast cancer and 30 percent were men. About 8 percent of the female volunteers
(302 of 3,742) were breast or ovarian cancer survivors.
The impetus for the study was a discovery in 1995 by the same investigators that one of the alterations (185delAG) in BRCA1 was present in an unusually high proportion of stored blood samples from the general Jewish population. However, since the cancer histories of the donors were not known, it was not possible to estimate the cancer risk associated with the alteration.
Since then, two additional alterations in BRCA1 and BRCA2 were reported in the Ashkenazi Jewish population. In the new study, testing for all three alterations, the researchers were able to compare the cancer histories of the relatives of persons with an alteration to the histories of those without an alteration, and thereby estimate the cancer risk associated with each alteration.
Each of the 5,318 volunteers donated a blood sample from a finger-prick and filled out a brief family history of cancer. DNA from the blood samples was tested for three alterations: two in the BRCA1 gene (185delAG and 5382insC) and one in the BRCA2 gene (6174delT).
The DNA analysis showed that 120 of the volunteers had one of the three mutations, and no individual carried more than one of the three. Forty-one (0.8 percent) carried the 185delAG mutation; 20 (0.4 percent) carried the 5382insC mutation and 59 (1.2 percent) of the participants carried the 6174delT deletion in BRCA2, for a combined frequency of 2.3 percent.
The number of people carrying a mutation was consistent with previous studies from the general Jewish population.
The authors also noted that the cancer risks in this study are likely to be overestimates because people with personal or family histories of breast cancer were more likely than others to volunteer for the study. They estimated, for example, that the true breast cancer risk for U.S. Ashkenazi women with an alteration may be 50 percent or lower.
"The data provides us with information about the average cancer risk among a group of carriers," said Margaret A. Tucker, M.D., chief of NCI's Genetic Epidemiology Branch. "We can't predict the risk for an individual carrier. The risk for breast cancer for an individual woman, for example, may be higher or lower than the 56 percent average."
The researchers calculated that only about 7 percent of the breast cancer in Jewish women is due to these alterations in BRCA1 and BRCA2. Likewise, the vast majority of breast cancers in non-Jewish women are not due to inherited alterations in these genes.
Many of the more than 100 alterations in each of the BRCA1 and BRCA2 genes identified in cancer-prone families are unique to a single family. In a few circumstances, identical alterations have been found in multiple families. In 1994 NIH scientists observed that three high-risk Ashkenazi families that were not known to be related carried an identical alteration (185delAG). This was the first alteration associated with a particular ethnic group. Besides Ashkenazi Jews, recent studies reported mutations that may be unique to Norwegian, Icelandic, or Dutch families.
To date, no other ethnic-specific mutation in the United States has been discovered with as high a frequency as the ones specific to Ashkenazi Jews. The frequency (1 in 44) reported in this and other studies is at least several times higher than estimates of all the mutations in BRCA1 and BRCA2 for the general U.S. population. The high frequency of these three mutations made it possible to conduct the current study with a relatively small number of volunteers.
Although volunteers in the study will not receive their individual results, they will, if requested, receive a summary of the overall results of the study.
NIH researchers are in the process of developing a follow-up study in the local Jewish community with an option to be tested and receive individual test results for these three mutations in BRCA1 and BRCA2, after counseling as to the risks and benefits of genetic testing. This study will also try to define risk factors, in addition to these mutations, that may modify a person's chance of developing breast, ovarian, or prostate cancer. These factors may include hormone exposure or other genetic alterations.
* The study is titled "The Risk of Cancer Associated With Specific Mutations of BRCA1 and BRCA2 Among Ashkenazi Jews." The authors are Jeffery P. Struewing, Patricia Hartge, Sholom Wacholder, Sonya M. Baker, Martha Berlin, Mary McAdams, Michelle M. Timmerman, Lawrence C. Brody, and Margaret A. Tucker, Vol. 336, No. 20, pp. 1401-1408, May 15, 1997.
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