Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic

Abstract

Background: A mutation found in the BRCA1 or BRCA2 gene of a breast tumor could be either germline or somatically acquired. The prevalence of somatic BRCA1/2 mutations and the ratio between somatic and germline BRCA1/2 mutations in unselected breast cancer patients are currently unclear.

Patients and methods: Paired normal and tumor DNA was analyzed for BRCA1/2 mutations by massively parallel sequencing in an unselected cohort of 273 breast cancer patients from south Sweden.

Results: Deleterious germline mutations in BRCA1 (n = 10) or BRCA2 (n = 10) were detected in 20 patients (7%). Deleterious somatic mutations in BRCA1 (n = 4) or BRCA2 (n = 5) were detected in 9 patients (3%). Accordingly, about 1 in 9 breast carcinomas (11%) in our cohort harbor a BRCA1/2 mutation. For each gene, the tumor phenotypes were very similar regardless of the mutation being germline or somatically acquired, whereas the tumor phenotypes differed significantly between wild-type and mutated cases. For age at diagnosis, the patients with somatic BRCA1/2 mutations resembled the wild-type patients (median age at diagnosis, germline BRCA1: 41.5 years; germline BRCA2: 49.5 years; somatic BRCA1/2: 65 years; wild-type BRCA1/2: 62.5 years).

Conclusions: In a population without strong germline founder mutations, the likelihood of a BRCA1/2 mutation found in a breast carcinoma being somatic was ∼1/3 and germline 2/3. This may have implications for treatment and genetic counseling.

Keywords: breast cancer; carrier; germline; mutation; prevalence; somatic.

Figure 1.

(A) Study flowchart. Approximately 80% of all patients diagnosed with invasive breast cancer in Malmö between 2007 and 2009 were included in the All Breast Cancer in Malmö (ABiM) study. Patients not included were either not asked, ineligible, could not be consented due to language difficulty, or declined to participate. As a result, 538 patients were included in the ABiM study during that period. With the limitation of tumor and normal DNA of sufficient sequencing quality, we were able to study BRCA1 and BRCA2 mutations in 273 patients. (B) BRCA1 and BRCA2 mutations by protein position. Single-nucleotide variants and small (≤5 bp) indels mapped to the canonical protein sequence are shown. blue, germline mutations. Dark Green, somatic mutations. Protein domains are shown as colored bars. BRCT, BRCA1 C-terminus; EIN3, ethylene insensitive 3; OB, oligonucleotide/oligosaccharide-binding. (C) Distribution of the PAM50 intrinsic subtype across mutation subgroups. BRCA1 germline mutant tumors have a similar subtype distribution as BRCA1 somatic mutants, whereas BRCA2 germline and somatic mutants are similar to BRCA1/2 wild-type tumors.