The high prevalence of BRCA "breast cancer" genes in Ashkenazi Jews has been known for two decades – and the incidence could be higher than the global average among Palestinians as well, for reasons that are related, scientists say. Israel needs to make testing free, easy to obtain and faster, too, for susceptible populations, they add.
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One in 40 Ashkenazi Jews in Israel and the UK, or, 2.5% of Ashkenazi Jewish women, carry a mutation in one or the other of two "breast cancer" genes, BRCA1 and BRCA2.
All Ashkenazi Jewish women in Israel should be offered a test for potentially-fatal breast cancer genes in the healthcare basket, urges Professor Ephrat Levy-Lahad, director of the Medical Genetics Institute at Shaare Zedek Medical Center in Jerusalem. Women in Israel are typically tested for these genes only after being diagnosed with breast cancer, “an obvious failure of cancer prevention,” Levy-Lahad mourns.
In the past, testing for presence of the genes in Israel and in the U.S. was confined to women with an extensive family history of the disease, or among those who developed it at a young age. Yet about 51 percent of women who carry these mutations have no family history of breast or ovarian cancer, which argues for broader testing for the sake of prevention.
Both ovarian and breast cancer can be prevented by preemptive surgery.
Surgical removal of the ovaries, or oophorectomy, is associated with an 80 percent reduction3 in the risk of ovarian and fallopian tube cancers in BRCA1/BRCA2 carriers.
“Depending on your age, removal of the ovaries and fallopian tubes has been shown to reduce total mortality; oophorectomy in carriers reduces death, period, from everything,” Levy-Lahad says. “Your chances of dying, from any cause, if you are a carrier, are dramatically reduced if you have your ovaries removed.”
(According to a 2014 paper, Impact of Oophorectomy on Cancer Incidence and Mortality in Women With a BRCA1 orBRCA2 Mutation, “The striking finding in this study of BRCA1 or BRCA2 mutation carriers was the effect of oophorectomy on all-cause mortality." Among women who did not have cancer when joining the study, the risk of death in the follow-up period fell by 77% after oophorectomy. The reason is partly reduced incidence of ovarian, tubal, and peritoneal cancers as well.)
BRCA1 and BRCA2 are genes that code for proteins that repair breaks in DNA, in particular “double-strand breaks” where both chromosomes in a pair are disabled. (A recent study also shows that BRCA1 is depleted in people with Alzheimer’s disease: the gene “critically contributes” to repair of double-strand-breaks in neurons, as well.)
Very high cancer risks, for men too
Women who carry a mutation in either gene have very high cancer risks. Those who carry the BRCA1 mutation have a 60 percent risk of developing breast or ovarian cancer by age 60, and an 83 percent chance of developing either disease by age 80; those who carry BRCA2 have a 33 percent risk of developing either cancer by age 60, or a 76 percent chance by age 80.
Male carriers of BRCA2 mutations are two to six more likely than average to develop prostate cancer. But clinical screening for BRCA1/2 mutations is not recommended for men, Levy-Lahad notes, since in any case, there is no known way to reduce prostate cancer risk or mortality. "The estimates for prostate cancer risk are very variable," Levy-Lahad elaborates. "It is not clear that BRCA1 significantly increases prostate cancer risk, and BRCA2 probably increases prostate cancer risk by about twofold. In any case, there are no measures that have been shown to reduced morbidity or mortality from prostate cancer, so in the clinical context (as opposed to research) we cannot at this point justify screening for BRCA1/BRCA2 mutations to reduce prostate cancer risk."
Together with her colleagues in the Israel Breast Cancer Study, Levy-Lahad is planning to study how common BRCA1/BRCA2 mutations are among non-Ashkenazi Jews. Current estimates suggest that one-in-three hundred to one-in-four hundred non-Ashkenazi Jews carry them; the prevalence in the general population is between 1 in 400 and 1 in 800.
A small group of ancestors
Ashkenazi Jews—women and men both—carry BRCA mutations at a greater frequency than others because of a phenomenon called the founder effect: They are descended from a small, geographically-isolated community of European ancestors who married among themselves, preserving and passing down these harmful traits.
Palestinians may carry BRCA genes at higher rates than average as well, according to Moien Kanaan, professor of genetics at Bethlehem University in the Palestinian Authority. The higher prevalence may have the same root cause.
“The Palestinian population has a unique structure,” Kanaan explains. “Around 40 percent of people are marrying within the extended family,” which, because of reduced genetic variation among the population, can increase susceptibility to inherited diseases, including cancer.
Breast cancer is on the rise among Palestinians, Kanaan notes, and is the most prevalent form of cancer among the population. He is collaborating with Levy-Lahad and Mary-Claire King, Professor of Medical Genetics at the University of Washington in Seattle, on the Middle East Breast Cancer Study, one of whose goals is to “determine the inherited predisposition to breast cancer in the Palestinian Arab population.”
Within the framework of the Middle East Breast Cancer Study, Kanaan has enrolled 1,600 breast cancer patients from the West Bank and Gaza, about 30 percent of whom have a family history of the disease. His team is in the process of testing these subjects and their relatives not just for BRCA1/BRCA2 genes—which account for about 20 to 25 percent of hereditary breast cancers4—but also for dozens of other breast cancer genes with names like ATM and CHEK2.
BRCA1 and BRCA2 are particularly prone to disruption because, to quote Mary-Claire King, they live in “bad neighborhoods” on chromosomes, where rogue genetic elements can insert themselves into the gene and shut it down with relative ease. “Hotspots—sites in our genome that are subject to change—are independent from anything else; they don’t follow a particular lineage, theological or ideological in any way,” Kanaan points out.
Screening programs for Palestinians—not just among those women who are diagnosed with the disease, but for their relatives as well—have led to a shift in attitude among families at risk for breast and ovarian cancer, Kanaan says. “People before, they take it as if it’s God’s will or God’s plan for somebody to develop a cancer and die from cancer. But nowadays we could pinpoint the fact that there is a risk; that risk can be looked at before the actual incidence of cancer, and either manage or prevent it,” with drugs like tamoxifen and regular mammograms or magnetic resonance imaging.
In Israel itself, about 270 to 280 cases of breast or ovarian cancer could be prevented each year if BRCA1/BRCA2 carriers were identified before they became ill and if 90 percent of the carriers opted for oophorectomy, Levy-Lahad says.
Probably for cultural reasons, only about 15 percent of carriers opt for double mastectomy in Israel, she notes. That rate far is far lower than in the U.S., where medical care tends to be more aggressive.
Currently, the wait for BRCA testing may be up to a year, and that’s why Levy-Lahad is pushing for BRCA1/2 tests to be included in healthcare baskets. Advisory committees to the Ministry of Health are considering this option, she says.
“Right now, if you are a healthy Ashkenazi woman, you need to have a really severe family history to receive testing through the health system,” she notes. “We are trying to bring to the Israeli medical system’s attention that there is a real bottleneck in terms of genetic counseling and genetic testing, and it’s ridiculous that it takes a year.” Just as Israel has very successfully screened carriers for childhood genetic diseases like Tay-Sachs and cystic fibrosis, so, says Levy-Lahad, should the country consider screening for adult genetic diseases as well. “Breast cancer and ovarian cancer is one place where it can be done.”