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Original Investigation
December 2017

Genetic Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 Founder Alleles Among Ashkenazi Jewish Women

Author Affiliations
  • 1Division of Medical Genetics, Department of Medicine, University of Washington, Seattle
  • 2Department of Genome Sciences, University of Washington, Seattle
  • 3Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle
JAMA Oncol. 2017;3(12):1647-1653. doi:10.1001/jamaoncol.2017.1996
Key Points

Question  Among patients of Ashkenazi Jewish ancestry with breast cancer who do not carry one of the founder mutations in BRCA1 or BRCA2, what is the likelihood of carrying another cancer-predisposing mutation in BRCA1, BRCA2, or another breast cancer gene?

Findings  In this cohort study, 1007 patients of Ashkenazi Jewish ancestry with breast cancer were evaluated by multiplex genomic sequencing for all known and candidate breast cancer genes. Among patients without a founder mutation in BRCA1 or BRCA2, 0.8% carried a different mutation in BRCA1 or BRCA2 and 3.4% carried a mutation in another gene.

Meaning  Ashkenazi Jewish patients with breast cancer can benefit from genetic testing for all breast cancer genes.

Abstract

Importance  Among Ashkenazi Jewish women, 3 mutations in BRCA1 and BRCA2 severely increase the risk of breast and ovarian cancer. However, among Ashkenazi Jewish patients with breast cancer who do not carry one of these founder mutations, the likelihood of carrying another pathogenic mutation in BRCA1 or BRCA2 or another breast cancer gene is not known. This information would be valuable to the patient and family for cancer prevention and treatment.

Objective  To determine the frequency of cancer-predisposing mutations other than the BRCA1 and BRCA2 founder alleles among patients of Ashkenazi Jewish ancestry with breast cancer.

Design, Setting, and Participants  In this cohort study, genomic DNA of women from 12 major cancer centers with a 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 was sequenced for known and candidate breast cancer genes. Data analysis was performed from July 10, 2014, to March 10, 2017.

Main Outcomes and Measures  Genomic DNA from all 1007 NYBCS probands was sequenced for 23 known and candidate breast cancer genes using BROCA, a targeted multiplexed gene panel.

Results  Of the 1007 probands in the study, 903 probands had no founder mutations in BRCA1 or BRCA2; of these probands, 7 (0.8%) carried another pathogenic mutation in BRCA1 or BRCA2, and 31 (3.4%) carried a pathogenic mutation in another breast cancer gene (29 in CHEK2, and 1 each in BRIP1 and NBN). Of all inherited predispositions to breast cancer in the NYBCS, 73.8% (104 of 142) were due to a BRCA1 or BRCA2 founder allele, 4.9% (7 of 142) to another BRCA1 or BRCA2 mutation, and 21.8% (31 of 142) to a mutation in another gene. Overall, 14.1% (142 of 1007) of Ashkenazi Jewish patients with breast cancer in the NYBCS carried a germline mutation responsible for their disease: 11.0% (111 of 1007) in BRCA1 or BRCA2, and 3.1% (31 of 1007) 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 and 54 patients (48.6%) did not.

Conclusions and Relevance  Comprehensive sequencing would provide complete relevant genetic information for Ashkenazi Jewish patients with breast cancer.

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