Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer

Abstract

Purpose: Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC.

Patients and methods: Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations.

Results: Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P < .001) and had higher-grade tumors (P = .01) than those without mutations.

Conclusion: Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives.

Fig 1.

Germline likely deleterious mutations from 14 breast cancer predisposition genes in unselected patients with triple-negative breast cancer. Locations of likely deleterious mutations and domains in proteins encoded by predisposition genes are shown by lollipop structures. Mutations are labeled, other than in BRCA1 and BRCA2. Protein domain patterns are shown in key. Scales on genes reflect number of amino acid residues.

Fig 2.

Age at onset of triple-negative breast cancer by mutation status. Distribution shown for patients with triple-negative breast cancer with BRCA1, BRCA2, and other non-BRCA1/2 mutations and no mutations (ie, wild type [WT]).

Fig 3.

Tumor characteristics of patients with triple-negative breast cancer by mutation status. Proportion of those with BRCA1, BRCA2, and other non-BRCA1/2 mutations and no mutations (ie, wild type [WT]) exhibiting specified nodal status, tumor stage, tumor grade, and bilateral breast cancer status.