Ethnic Status and Mutation Prevalence - Hereditary Breast Cancer

Ethnic status strongly influences the probability of detecting a mutation in BRCA1 or BRCA2. In the United States, Jewish women do not, as a group, manifest a significantly increased risk for breast or ovarian cancer; however, Jewish women who have a close relative affected with breast or ovarian cancer appear to be at greater risk than non-Jewish women with an affected relative.

It has been suggested that the increased familial risk of breast or ovarian cancer among Jewish women is related to an increased prevalence of BRCA1 or BRCA2 mutations in this population.

In 1996, Tonin et al described a recurring BRCA1 mutation (185delAG, also known as 187delAG) in breast cancer patients of Ashkenazi (Central and Eastern European Jewish) descent (reviewed in ref. 16).

Table 11.1. Indicators of increased probability of detecting BRCA mutations

  • Multiple cases of early-onset breast cancer
  • Bilateral breast cancer
  • Ovarian cancer and breast cancer in the same family
  • Ovarian cancer and breast cancer in the same woman
  • Male and female breast cancer in the same family

Several groups quickly demonstrated that up to 20% of Ashkenazi women with early-onset breast cancer carry this mutation. Soon thereafter, a recurring BRCA2 mutation (6174delT) was identified in an additional 8% of Ashkenazi women with early-onset breast cancer.

The high prevalence of these specific mutations among young breast cancer patients of Ashkenazi descent is a reflection of a remarkably high prevalence of these same changes in the Ashkenazi population as a whole. Population studies have indicated that 2.5% of unselected individuals of Ashkenazi descent carry one of three recurrent mutations (the two described above or a third, BRCA1 5382insC, also known as 5385insC). This high population prevalence is presumably the result of a “founder effect” in the ancestral European population. Unpublished series of Ashkenazi women with breast cancer (not selected for age at onset or family history) indicate that approximately 10% of women from this population have one of these three germline mutations.

Founder mutations are even more common in women of Ashkenazi descent with ovarian cancer. In unselected series, nearly 28% of Ashkenazi women with ovarian cancer (all ages) have one of the two BRCA1 mutations, and approximately 12% of those tested have BRCA2 6174delT. Collaborative series have shown that families of Ashkenazi descent with two or more breast cancers (at least one occurring before age 50) have a 29% likelihood of transmitting a founder mutation. If there is at least one case of ovarian cancer in the family, the probability of finding one of these mutations rises to 73%.

Interestingly, mutations appear to be less common in Ashkenazi women with DCIS (although still greater than in the general Ashkenazi population) and do not appear to occur with increased frequency in women with borderline ovarian tumors. Although these specific mutations are responsible for the majority of BRCA1 or BRCA2 alterations identified in this population, it is important to note that other mutations have been described in individuals of Ashkenazi descent. Hence, Ashkenazi families with pedigrees that are strongly suggestive of a hereditary breast or breast-ovarian cancer syndrome, but who do not appear to transmit one of the three founder mutations, should be offered more complete analysis of BRCA1 and BRCA2.

Mark E. Robson
Breast conservation therapy for invasive breast cancer in Ashkenazi women with BRCA gene founder mutations. J Natl Cancer Inst 2003


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