Newly Identified Genetic Mutations found in Ashkenazi Jewish Women with Breast Cancer

Comprehensive sequencing for all breast cancer genes may provide complete relevant genetic information for Ashkenazi Jewish patients, according to a new article published by JAMA Oncology.

Researchers in Seattle report that three mutations in BRCA1 and BRCA2 significantly increase the risk of breast cancer and ovarian cancer in Ashkenazi Jewish women. However, the likelihood of carrying another pathogenic mutation in BRCA1 or BRCA2 or another breast cancer gene until now has not been thoroughly investigated.

Mary-Claire King, PhD, of the University of Washington, Seattle, and coauthors sequenced genomic DNA of 1,007 women of Ashkenazi Jewish ancestry with breast cancer for known and candidate breast cancer genes. Of the 1,007 patients in the study, 903 had none of the three founder mutations in BRCA1 or BRCA2. Among those 903 patients, 7 patients (0.8%) carried a different mutation in BRCA1 or BRCA2 and 31 patients (3.4%) carried a damaging mutation in another breast cancer gene, according to the analysis.

In the group of 31 patients with another breast cancer gene, an analysis showed 29 patients had a pathogenic mutation in CHEK2, 1 patient had a mutation in BRIP1, and 1 patient had an NBN mutation.

“When you have a suspicion of familial breast cancer in a patient of Ashkenazi ancestry, further testing beyond the well-known Ashkenazi founder BRCA1 and BRCA2 pathogenic variants, particularly evaluation of CHEK2, may be productive,” said Gail Jarvik MD, PhD, Professor and Head of Medical Genetics at the University of Washington School of Medicine in Seattle.

Dr. Jarvik was not involved in the present study but said the findings suggest a change in genetic testing for Ashkenazi Jewish women. “Often, only the three founder pathogenic variants are tested. More comprehensive testing should be considered,” Dr. Jarvik told OncoTherapy Network.

The researchers analyzed the genomic DNA of women from 12 major cancer centers. All women in the study had a first diagnosis of invasive breast cancer and identified themselves and all four grandparents as Ashkenazi Jewish. These women were part of the New York Breast Cancer Study (NYBCS) from 1996 to 2000 and underwent sequencing for known and candidate breast cancer genes.

The researchers used a targeted multiplexed gene panel and sequenced for 23 known and candidate breast cancer genes. The study showed 142 (14.1%) of 1,007 women of Ashkenazi Jewish patients with breast cancer carried a germline mutation responsible for their disease: 11% (111 patients) in BRCA1 or BRCA2, and 3.1% (31 patients) 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 cancer or ovarian cancer and 54 patients (48.6%) did not, according to the study.

The authors note that this analysis had limitations, including that only genes known or suspected to harbor mutations that increase the risk of breast cancer were sequenced.