In a recent report from the New York Breast Cancer Study, led by BCRF investigator Mary Claire King, testing for breast cancer risk using a multigene panel was carried out for 1,007 Ashkenazi Jewish women with breast cancer. Of this group, 104 women carried one of the three well-known “Jewish mutations” in BRCA1 or BRCA2, while 903 women (nearly 90%) did not. Dr King and her team evaluated what other mutations might be responsible for breast cancer in these women.
They found that seven women (about 1%) had other mutations in BRCA1 or BRCA2. These mutations were extremely rare: each were found in only one or a few families worldwide. Another 31 women (about 3%) carried mutations in other known breast cancer genes, almost all in the gene named CHEK2. The CHEK2 gene has been very extensively studied, both in the Jewish population and more generally. Mutations in CHEK2 double the risk of breast cancer, a significant increase, but not nearly as severe as the more than ten-fold increase in risk due to mutations in BRCA1 or BRCA2.
Of all women with a mutation in any breast cancer risk genes, about half did not have any known family history of breast or ovarian cancer.
Mutations in the genes BRCA1 and BRCA2 are the most common cause of hereditary breast cancer. Among women of Ashkenazi Jewish heritage, about 11 percent of all breast cancers are caused by one of only three BRCA1 or BRCA2 mutations. These three mutations are called founder mutations, because they are ancient mutations in the Ashkenazi Jewish world, so were “founded” in that community, and thus appear in many modern Ashkenazi Jewish families.
“These three founder mutations have been well known for 20 years,” Dr. King commented, “in large part due to studies supported by BCRF.
“The goal of this recent study,” she continued, “was to determine how often breast cancer among Ashkenazi Jewish patients was explained by inherited mutations other than these three founder mutations. The answer was: not a lot, but enough to suggest that testing for other mutations with a multigene panel might be wise for women whose cancer is not explained by one of the founder mutations.”
Dr. King emphasized that for most women of Ashkenazi Jewish ancestry who do not carry one of the founder mutations in BRCA1 or BRCA2, a breast cancer diagnosis is unlikely to be due to inherited predisposition. Any woman can resolve the question for herself by testing all breast cancer genes. Nowadays this is easily done.
“It is so inexpensive to be tested for any breast cancer gene,” she added, “that this may be the approach of choice for women of Jewish ancestry and indeed all women who develop breast cancer,” Dr. King said on the JAMA Oncology podcast.
In ongoing work, Dr. King and colleagues are now looking at more cryptic areas of the genome, called non-coding DNA, to identify mutations that regulate gene expression. She believes that alterations to these regulatory areas might explain breast cancer in families, of any ancestry, with no mutations in any of the known breast cancer genes
You can read more about the BCRF research of Drs. King, Levy-Lahad and Kanaan on our researchers page.
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