 Ashkenazi Jews and Genetic Risk BRCA Mutation Carriers With Breast Cancer Often Opt to Have Ovaries Removed Breast and Ovarian Cancer Genetic Diseases in Askenazi Jews Ashkenazi Jews and Genetic RiskTo mark April's Minority Cancer Awareness Week cancerpage.com took a month-long look at the racial disparity in cancer outreach, cases, care, and research. This article considers Ashkenazi Jews and their special genetic risks. By Richard A. Zmuda In late 1994, researchers from the National Institutes of Health were studying three families of Ashkenazi Jews that had an extremely strong history of breast cancer. The families were not known to be related, but they each carried an identical mutation on a specific gene called BRCA1. This was the first genetic mutation positively associated with cancer risk in a particular ethnic group. Since then, other alterations have been identified that occur in Icelandic, Norwegian and Dutch populations, among others. The Ashkenazi JewsAshkenazi Jews in the United States are descended from eastern or central European Jews. Since immigrating to this country, they have maintained an extremely close-knit community and usually marry within their group. For scientists the group provides a well-defined genetic lineage. Furthermore, Ashkenazi Jews have tended to cluster geographically in different sections of the country, including upstate New York and the greater Cleveland area. (Ashkenazi Jews comprise over 90 percent of the total Jewish population in Cleveland.)Because of their identifiable genetic mutation and the close geographic clustering of their population, Ashkenazi Jews represent an ideal study group for cancer researchers. And yet, cautions Dr. Charles Weijer of Dalhousie University in Halifax, Nova Scotia, those same qualities could also result in undue harm. Writing in the journal Nature Genetics, Weijer argued for guidelines to protect less organized, more vulnerable ethnic communities. For example, he noted that the Ashkenazi Jewish community has no centralized and organized political representation. Therefore, researchers may have difficulty obtaining legitimate “consent from the community at the start of a study, community consent for protocol changes, the right for the community to withdraw from the study, consent for further use of the sample data, consent to identify the community in print, and community consent for media interviews.” Weijer called on researchers to be more culturally sensitive when working with such communities and he suggested guidelines for involving the participants in decisions about the protocol of a study and tailoring informed consent to the individual community’s cultural practices. Breast Cancer RiskWhile genetic causes are linked with only about five to ten percent of total breast cancer cases, the disproportionately high prevalence of BRCA1 and BRCA2 mutations among Ashkenazi Jewish women means that they are at much greater risk of developing breast (and ovarian) cancer during their lifetime.A follow-up study by National Institutes of Health researchers in 1996 found that women carrying one of the BRCA1 or BRCA2 mutations had on average a 56 percent chance of getting breast cancer by the age of 70, (compared with a 13 percent chance without the alterations). These women also had a 16 percent chance of getting ovarian cancer (compared with a 1.6 percent chance for non-carriers). In other words, the researchers estimated that by the age of 70, slightly more than half of all women with a BRCA1 or BRCA2 alteration will develop breast cancer and about one out of every six carriers will develop ovarian cancer. Another article in Nature Genetics identified a new genetic mutation called APC that was found to modestly increase the risk of hereditary breast cancer in women of Ashkenazi Jewish descent. The researchers from Memorial Sloan-Kettering Cancer Center in New York said the risk was lower when only the APC genetic defect was involved. However, the increased risk was much more significant for women who also had BRCA mutations. Not Just Breast Cancer AnymoreNIH researchers have also confirmed a link between prostate cancer and men carrying an aberration of the BRCA1 gene. It was estimated that men carrying this mutation have on average a 16 percent chance of getting prostate cancer by the age of 70, compared with a 1.6 percent chance for non-carriers. In other words, by age 70 the researchers estimate that about one out of every six men carrying a BRCA mutation will develop prostate cancer.A study presented at a recent meeting of the American College of Gastroenterology suggested that the APC genetic mutation already linked to breast cancer in Ashkenazi Jewish women may also be associated with a greater risk of colon cancer. Researchers at the Cleveland Clinic Foundation noted that Ashkenazi Jews with a family history of colon cancer—who themselves develop colon cancer—are also younger at the time of diagnosis and are more likely to have cancers located in the proximal (right side) of the colon. Genetic CounselingEven if a woman has a family history of breast cancer, or is associated with a higher-risk ethnic population, the value of genetic testing remains highly controversial. Studies show that when women are asked what they would do in the hypothetical situation of learning that they express high-risk breast cancer genes, the overwhelming majority says they would decline prophylactic mastectomy—a mastectomy undertaken without clinical signs of breast cancer. Instead they would opt for increased screening and surveillance.But such distressing genetic news also results in significant, long-term anxiety for the patient. Furthermore, there are legitimate questions about keeping such a finding confidential. "Knowing that cancer could occur because of a positive genetic test can be severely anxiety-provoking," said Jennifer Stein, a genetic counselor with the Cleveland Clinic Foundation. In an interview with cancerpage.com she said, “It can be even more distressing because it opens up the risk that cancer might occur in other family members." "However," Stein added, "it can also be empowering. You now know that you face a risk, but you also have an opportunity to minimize that risk." How private would information from genetic testing be? According to a study presented at a meeting of the Society of Human Genetics conference, a majority of genetic counselors would pursue genetic testing for themselves but would keep test results off their medical records. Ellen Matoloff of the Yale Cancer Center in New Haven, Connecticut and colleagues from the Yale University School of Medicine surveyed 296 genetic counselors belonging to the National Society of Genetic Counselors to determine their fears of genetic discrimination. The majority said they would pursue testing for hereditary genes if they had a 50 percent chance of being carriers. But two-thirds of them said they would not bill their health insurance company for such testing, and one-quarter of them said they would use an alias. In spite of such privacy concerns, experts almost universally agree on the importance of genetic counseling once a genetic marker for cancer has been identified. There are often many complex psychosocial and economic issues that a patient must suddenly cope with. And the resultant emotional burden may actually overwhelm the genetic risk. Credit BRCA Mutation Carriers With Breast Cancer Often Opt to Have Ovaries RemovedBy Karla Harby NEW YORK, September 27, 2000 (Reuters Health) — Almost half of women with breast cancer who are Ashkenazi Jews and who find out they are carriers of BRCA1 or BRCA2 gene mutations opt to have their healthy ovaries surgically removed, according to cancer experts at Memorial Sloan-Kettering Cancer Center in New York. Ovary removal is a drastic surgery that can shut down estrogen production and put women into premature menopause. However, BRCA carriers are at higher risk of ovarian cancer, and ovary removal may help ward off the disease. Inherited mutations cause about 10% of ovarian cancer cases, and certain mutations are more common in women of eastern European descent, known as Ashkenazi Jews. Of the 190 breast cancer patients who were found to have cancer-causing BRCA mutations at Memorial Sloan-Kettering Cancer Center to date, 85 chose to have their apparently healthy ovaries removed as a cancer-prevention measure, said Dr. Kenneth Offit, chief of the clinical genetics service. The median age of this group was 40 to 46. What's more, researchers discovered four cases of ovarian cancer in the ovaries and three of these patients had "totally normal" ultrasound examinations — the diagnostic imaging test thought to be best for detecting the disease. "I hope that these lives are saved," Offit said. "We think there's an 80% to 90% cure rate" when ovarian cancer is detected so early. But Offit noted that in rare cases, patients who have had their ovaries removed will go on to develop cancer in the tissue near the ovaries. Speaking at a conference hosted by the American Jewish Congress, Offit suggested there is more optimism now when BRCA mutations are discovered than there was a few years ago. "Genetic discrimination has been overplayed, and the tests are being reimbursed by insurers," he said. In addition, ongoing clinical trials look promising for women with mutations of the BRCA genes or a family history of breast cancer. Offit noted that the Ashkenazi Jews are only one of many groups that have a genetic predisposition to particular cancers. "Within the Jewish community, this represents an opportunity to demonstrate to the world the careful use of this (genetic) information," he said. Ashkenazic Lineage and Risk of Breast CancerResearchers have studied the connection of specific genes or a damaged gene and its influence of increasing risk of breast cancer. Recently two breast cancer genes fitting this description were discovered — BrCa 1 and BrCa 2. Fortunately, the occurrence of these genes is very uncommon.Today, over 200 mutations or abnormalities have been identified on one or other of these two genes. Subsequent research has identified that specific mutations of these genes have an increased frequency in families with common ancestral backgrounds. Approximately 0.9 percent of the Ashkenazi population (Northern and Central European Jews) carries a single BrCa 1 mutation known as 185delAG. By comparison, among the general population only 0.12 percent of women carry any mutation in BrCa 1 or BrCa 2. Of Ashkenazi women who have developed breast cancer approximately 20 percent have been found to have this specific mutation. Other mutations have also been identified as having increased frequency in Ashkenazi women including the 5382insC mutation in BrCa1 and 617delT in BrCa 2. Because of the increased incidence of these three specific mutations and the associated increase in early breast cancer, Jewish women have many concerns about the risk of breast cancer. Because of this, gene-testing laboratories offer a short genetic screen for just these three mutations. One study published in the May 1997 issue of the New England Medical Journal reported that over 2 percent of Ashkenazi Jews carry mutations in BrCa 1 and BrCa2. This is an important study of over 5,000 people who were not selected because of their cancer status but because of their lineage. Thus, we can get a clearer picture of the extent of mutations in the two breast cancer genes and correlate this with a family history of breast cancer. Of this group, 120 carriers of the mutation were identified. By the age of 70, the estimated risk of developing breast cancer among these carriers was 56 percent (and 16 percent for ovarian cancer and 16 percent for prostate cancer). Scientists concluded that over 2 percent of Ashkenazi Jews carry mutations of these breast cancer genes. Recent updates of this study reduce prevalence to 1.5 percent. There is also evidence that the strength of the genetic mutation is not as strong as originally thought. This is a rapidly changing field and new data is published frequently. Breast and Ovarian Cancer Genetic Diseases in Askenazi JewsBy Lauren John, MA, MLS Ashkenazi is the term used to describe Jews who have ancestors from Eastern or Central Europe. Today, there are Ashkenazi Jews all over the world and many are intermarrying. But for centuries, political and religious factors ensured their genetic isolation from the population at large. As is the case with other groups who live, or lived, in relative isolation — such as the French Canadians and Icelanders — scientists theorize that most Ashkenazi Jews can trace their ancestry back to a small number of founders. The founder theory is of particular interest to geneticists because they theorize that even if just a few of these founders had a mutation, the mutation would become amplified in the population. This theory is supported by the fact that today people of Ashkenazi Jewish descent have a higher incidence of a number of specific mutations, for example mutations in the genes that increase the risk of developing breast and ovarian cancer, and mutations that cause the childhood neurological disease Tay-Sachs disease.
Origins of the Ashkenazi JewsThe word Ashkenazi is derived from the Hebrew word for "Germany". Today, the term is used to refer to Jews who have ancestors from Eastern or Central Europe, such as Germany, Poland, Lithuania, Ukraine, and Russia.Scholars disagree about how the Jews, living for thousands of years in the Middle East, first arrived in Eastern Europe. Some theorize that Mediterranean Jews, ca. 800 AD, were invited by the emperor Charlemagne to settle the Germanic territories. Not all of the Jews traveled that far east, however. (A separate group, the Sephardic Jews descend from ancestors in Spain and North Africa.) Ashkenazi Jews TodayToday, in the aftermath of World War II and the Holocaust, most of the world's 10 million Ashkenazi Jews live in the United States, Israel, South America, South Africa, Australia and New Zealand. About 80 percent of the six million ethnic Jews in the United States are of Ashkenazi Jewish descent.Some Genetic Diseases are More Common in Ashkenazi JewsAshkenazi Jews are at greater risk of developing several genetic diseases rarely found in the population as a whole. For example, Type 1 Gaucher disease — a nonlethal condition in which the body lacks a gene regulating the breakdown of a particular kind of fat — is one of the more common genetic disorders among Ashkenazi Jews. An estimated one in ten Ashkenazi Jews is a carrier for Gaucher disease. Carrying one mutated gene for the disease will not cause symptoms. However, if both parents carry one mutated gene, there is a one in four chance that their children will inherit two Gaucher genes and develop the disease.The childhood neurological disorder Tay-Sachs disease is also most commonly found in people of Ashkenazi descent; an estimated 1 in 31 Ashkenazi Jews carrying a gene for Tay-Sachs. Here again, both parents must have a copy of the mutated gene in order to pass on the disease to a child — and the child of two people who each carry one Tay-Sachs mutation has a one in four chance of receiving two mutated genes and developing the disease. Recent studies have shown that people of Ashkenazi Jewish descent may be at greater risk for breast and ovarian cancer than the general population. In addition, recent studies have shown that people of Ashkenazi Jewish descent may be at greater risk for breast and ovarian cancer than the general population. In 1995, scientists from the National Institutes of Health (NIH) discovered that a particular mutation in the breast cancer gene called BRCA1 was present in one percent of the general Jewish population. 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 to 0.6 percent. A follow up study in 1996 found two additional mutations (one in the BRCA 1 gene and one in another breast cancer gene called BRCA2) to have a greater prevalence in the Ashkenazi Jewish population, bringing the overall risk for carrying one of these three mutations to 2.3 percent. Why Do Ashkenazi Jews Get More Genetic Diseases? The Founder Effect TheoryMost of today's Ashkenazi Jews descend from a group of perhaps only a few thousand people. Stanford University geneticist Neil Risch explains the range of genetic diseases unique to the Ashkenazi Jewish population by theorizing that most of today's Ashkenazi Jews descend from a group of perhaps only a few thousand people — the privileged Ashkenazi that lived 500 years ago in Eastern Europe. The poorer Ashkenazi Jews, says Risch, had fewer children that lived to adulthood and, as a result, they did not pass on as many genetic conditions. Geneticists refer to this relatively small group of ancestors as founders.Given that until recently, both religious and political factors helped to ensure that Ashkenazi Jews married other Ashkenazi Jews, millions of people may be able to trace their ancestry directly to these founders. Thus, even if just a few founders had a mutation, the gene defect would become amplified in the population. Why Do Ashkenazi Jews Get More Genetic Diseases? The Beneficial Mutation TheoryOther geneticists theorize that diseases in Ashkenazi Jews have arisen because of hidden benefits linked to the inheritance of a single copy of a mutant gene. People who carried the Tay-Sachs gene may have been resistant to tuberculosis.For example, people with one copy of the Tay-Sachs gene were discovered to be resistant to tuberculosis, a condition common in the crowded ghetto conditions in which Ashkenazi Jews often lived. Geneticists theorize that the people who carried the Tay-Sachs gene may have survived better under ghetto conditions, whereas people without the gene would be more likely to die. As a result, the Tay-Sachs gene continued to be passed on in greater numbers in the Ashkenazi population. Today, with the tuberculosis threat largely gone, the gene threatens the Ashkenazi population because it is linked to serious and fatal childhood illness. But, historically, the gene was passed on because, although it threatened the lifespan of some children, it protected larger numbers of Ashkenazi Jews of all ages who were at risk for tuberculosis. Regardless of the origin of the mutations, people of Ashkenazi Jewish descent should be aware that they may be at increased genetic risk for certain conditions. This knowledge and screening has already decreased the number of children born with the fatal Tay Sachs disease by making carrier testing available to those who want to learn their status. Understanding these risks can lead to more accurate risk assessment, genetic testing, and preventive therapy. http://www.genetichealth.com/ |
