Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 in Ashkenazi Jewish Women

Key Points

  • Overall, 128 of 142 patients (90.1%) with a mutation in any gene carried a founder allele in BRCA1, BRCA2, or CHEK2.
  • A total of 14.1% carried germline mutations responsible for disease, consisting of BRCA1 or BRCA2 in 11.0% and CHEK2 or another breast cancer gene in 3.1%.

A cohort study in Ashkenazi Jewish women with breast cancer identified mutations other than BRCA1 and BRCA2 founder alleles that were associated with cancer risk. These study results were reported by Walsh et al in JAMA Oncology. Among Ashkenazi Jewish women, three mutations in BRCA1 and BRCA2 dramatically increase the risk of breast and ovarian cancers.

Study Details

In the study, genomic DNA sequences from 1,007 women from 12 major cancer centers with first diagnosis of invasive breast cancer who identified themselves and all 4 grandparents as Ashkenazi Jewish and participated in the New York Breast Cancer Study (NYBCS) from 1996 to 2000 were searched for 23 known and candidate breast cancer genes.

Frequency of Mutations

Of the 1,007 probands, 903 had no founder mutations in BRCA1 or BRCA2; of them, 7 (0.8%) carried another pathogenic mutation in BRCA1 or BRCA2, and 31 (3.4%) carried a pathogenic mutation in another breast cancer gene, including 29 in CHEK2 and 1 each in BRIP1 and NBN.

Of all 142 patients with inherited predisposition in the cohort (14.1%), 104 (73.8%) had a BRCA1 or BRCA2 founder allele, 7 (4.9%) had another BRCA1 or BRCA2 mutation, and 31 (21.8%) had a mutation in another gene. Overall, among the 14.1% of patients carrying a germline mutation that caused disease, 11.0% were in BRCA1 or BRCA2, and 3.1% were in CHEK2 or another breast cancer gene. Of the 111 patients with BRCA1 or BRCA2 mutations, 57 (51.4%) had a mother or sister with breast or ovarian cancer.

The investigators concluded: “Comprehensive sequencing would provide complete relevant genetic information for Ashkenazi Jewish patients with breast cancer.”

The study was supported by the Breast Cancer Research Foundation and by grants from the National Institutes of Health.

Mary-Claire King, PhD, of the University of Washington, Seattle, is the corresponding author of the JAMA Oncology article. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.




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