The 3 Common Ashkenazi Jewish Mutations in BRCA1/2: A Large Study of Cancer Risk and Risk Reduction
Many people are unaware that the frequency of BRCA1 and BRCA2 mutations in Ashkenazi Jews is ~1 in 40. This relatively high rate significantly impacts the Jewish community and is due to 3 common founder mutations:
- BRCA1 c.68_69delAG (often referred to as 185delAG or 187delAG)
- BRCA1 c.5266dupC (often referred to as 5382insC or 5385insC)
- BRCA2 c.5946delT (often referred to as 6174delT)
Because the 3 mutations are so common, they are generally tested for as a panel, as the first step in individuals with a personal and/or family history of breast or ovarian cancer and Ashkenazi Jewish ancestry.
A number of studies over the years have focused on cancer risks for carriers of the individual common Jewish mutations of BRCA1 and BRCA2, because they are common enough that it allows an attempt at analysis of risk for individual mutations rather than lumping all mutations of either BRCA1 or BRCA2 together. Among the more interesting results of these analyses is some support for the concept that there could be heterogeneity in cancer risk depending on the specific mutation involved. In particular, there is some previous evidence suggesting that women with the BRCA2 6174delT mutation may have a lower breast cancer risk than women with other BRCA2 mutations. Notably, the studies to date have mostly involved relatively small numbers of carriers of the individual mutations making it difficult to conclusively pin down any significant differences in risk by mutation. However, a new study, recently published online in the Journal of Clinical Oncology, takes a look at a significantly larger group of women adding to our knowledge in this area.
A New Study Looks at Cancer Risks in a Much Larger Number of Women with Common Jewish Mutations of BRCA1 and BRCA2
In the new study, an international team, led by Dr. Timothy Rebbeck of the University of Pennsylvania, studied 969 women with self-reported Jewish ancestry (from a total of more than 4700 women with deleterious BRCA1 or BRCA2 mutations from the Prevention and Observation of Surgical End Points [referred to as "PROSE"] Consortium. Many, but not all, of these women were identified prospectively, which strengthens the study. The researchers estimated breast cancer and ovarian cancer risks specific to each common Jewish BRCA1/2 mutation and also assessed whether risk reduction practices differed by mutation.
Some Key Results
There were a number of interesting results in this study. Here are a few:
1. The relative risk of breast cancer in this study was significantly lower for BRCA2 6174delT mutation carriers when compared to those women carrying other deleterious BRCA2 mutations. The “hazard ratio”* for breast cancer 6174delT carriers when compared to other BRCA2 mutation carriers was 0.35 (95% confidence interval was 0.18 to 0.69).
2. The researchers noted that the women with self-reported Jewish ancestry in this study were significantly more likely than women who did not report Jewish ancestry to pursue risk-reducing salpingo-oophorectomy (54% vs. 41%).
3. They also assessed whether there might be differences in cancer risk reduction downstream of risk-reducing salpingo-oophorectomy between women with different specific mutations. There were no significant differences.
Bottom Line for Women Carrying One of the Common Jewish BRCA1 or BRCA2 Mutations
1. This study provides further evidence supporting the concept that cancer risk can potentially vary depending on the specific mutation in BRCA1/BRCA2. Specifically, women with BRCA2 6174delT appear to have a lower risk of breast cancer than other BRCA2 mutation carriers (while still substantially elevated above the general population’s risk of breast cancer). That said, the researchers noted several caveats that could influence their data. Given the remaining uncertainty, they suggest that these results should not influence clinical care until they can be confirmed in further large prospective and population-based studies.
2. Differences in risk by mutation type will likely be a theme that will play out further in the next couple of decades or so. As our understanding of more individualized risks for BRCA1 and BRCA2 carriers increases, it may impact clinical care more significantly at some point in the future.
* The hazard ratio is a statistical expression of the chance of an event (breast cancer in this case) occurring in a particular group (BRCA2 6174delT mutation carriers for example) as a ratio of the chance of the event in a referent group (other BRCA2 mutation carriers). The hazard ratio is similar to relative risk in some respects, but there are some subtle differences that are beyond the scope of this blog post.
Selected References
Finkelman BS, Rubinstein WS, Friedman S, et al. Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers. Journal of Clinical Oncology 2012 (published online before print Mar 19 2012)
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