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Multicenter Study
. 2017 Dec 1;3(12):1647-1653.
doi: 10.1001/jamaoncol.2017.1996.

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

Tom Walsh  1   2 , Jessica B Mandell  1   2 , Barbara M Norquist  3 , Silvia Casadei  1   2 , Suleyman Gulsuner  1   2 , Ming K Lee  1   2 , Mary-Claire King  1   2
Affiliations
Multicenter Study

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

Tom Walsh et al. JAMA Oncol. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr King reported being an American Cancer Society Research Professor. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Relative Frequencies of Mutations in BRCA1, BRCA2, and Other Genes Among Ashkenazi Jewish Patients With Inherited Breast Cancer
Figure 2.
Figure 2.. Proportions of Ashkenazi Jewish Patients With Breast Cancer in the New York Breast Cancer Study With Damaging Mutations in BRCA1 or BRCA2 or in Another Breast Gene, by Age at Diagnosis and Family History of Breast or Ovarian Cancer
Figure 3.
Figure 3.. Family R in the New York Breast Cancer Study, With 3 Mutations in 2 Breast Cancer Genes
Participant IV-7 was diagnosed with her first breast cancer at 48 years of age, despite testing negative for BRCA2 6174delT, which had been identified in her cousins IV-1 and IV-3. Sequencing by BROCA revealed IV-7 to be compound heterozygous for 2 mutations in CHEK2, one or both of which were also present in each of her 3 affected sisters. The young women in generation V who carry one of the family’s 3 mutations can be offered screening appropriate to their genotypes. Dark blue symbols indicate affected individuals; white symbols, unaffected individuals; light blue symbols, other cancers; a diagonal slash, known deceased individuals; BilBr, bilateral breast cancer; Br, breast cancer; N, normal allele; Pan, pancreatic cancer; Pr, prostate cancer; St, stomach cancer; and V, variant allele.
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