Prevalence of BRCA1 and BRCA2 pathogenic variants in a large, unselected breast cancer cohort

Abstract

Breast cancer patients with BRCA1/2-driven tumors may benefit from targeted therapy. It is not clear whether current BRCA screening guidelines are effective at identifying these patients. The purpose of our study was to evaluate the prevalence of inherited BRCA1/2 pathogenic variants in a large, clinically representative breast cancer cohort and to estimate the proportion of BRCA1/2 carriers not detected by selectively screening individuals with the highest probability of being carriers according to current clinical guidelines. The study included 5,122 unselected Swedish breast cancer patients diagnosed from 2001 to 2008. Target sequence enrichment (48.48 Fluidigm Access Arrays) and sequencing were performed (Illumina Hi-Seq 2,500 instrument, v4 chemistry). Differences in patient and tumor characteristics of BRCA1/2 carriers who were already identified as part of clinical BRCA1/2 testing routines and additional BRCA1/2 carriers found by sequencing the entire study population were compared using logistic regression models. Ninety-two of 5,099 patients with valid variant calls were identified as BRCA1/2 carriers by screening all study participants (1.8%). Only 416 study participants (8.2%) were screened as part of clinical practice, but this identified 35 out of 92 carriers (38.0%). Clinically identified carriers were younger, less likely postmenopausal and more likely to be associated with familiar ovarian cancer compared to the additional carriers identified by screening all patients. More BRCA2 (34/42, 81.0%) than BRCA1 carriers (23/50, 46%) were missed by clinical screening. In conclusion, BRCA1/2 mutation prevalence in unselected breast cancer patients was 1.8%. Six in ten BRCA carriers were not detected by selective clinical screening of individuals.

Keywords: BRCA1; BRCA2; breast cancer; clinical testing; next-generation sequencing; prediction; screening criteria.

Figure 1

Mutation plot of BRCA1. Four and three splice variants for BRCA1 (NM_007294.3) are not shown.

Figure 2

Mutation plot of BRCA2. Three splice variants for BRCA2 (NM_000059.3) are not shown.

Figure 3

Overlap between women attending BRCA screening (clinically tested), BRCA carriers identified through selective clinical testing routine (clinically detected carriers) and BRCA carriers identified through screening all unselected LIBRO1 breast cancer patients (unselected‐detected). Of the 416 women who were clinically tested, 39 were found to be BRCA1/2 carriers (39/416, 9.3%). Our study confirmed 35 of these pathogenic variants. Four pathogenic variants were missed (BRCA1: c.4186‐1785_4,358‐1667dup and c.4358‐1729_4986 + 736dup; BRCA2: c.7805 + 1538_8331 + 560del and c.9097_9098insT). By sequencing the entire Swedish study, we found 55 more carriers who were not screened as part of clinical routine. [Color figure can be viewed at wileyonlinelibrary.com]