Clinical significance of large rearrangements in BRCA1 and BRCA2

Abstract

Background: Current estimates of the contribution of large rearrangement (LR) mutations in the BRCA1 (breast cancer 1, early onset) and BRCA2 (breast cancer 2, early onset) genes responsible for hereditary breast and ovarian cancer are based on limited studies of relatively homogeneous patient populations. The prevalence of BRCA1/2 LRs was investigated in 48,456 patients with diverse clinical histories and ancestries, referred for clinical molecular testing for suspicion of hereditary breast and ovarian cancer.

Methods: Sanger sequencing analysis was performed for BRCA1/2 and LR testing for deletions and duplications using a quantitative multiplex polymerase chain reaction assay. Prevalence data were analyzed for patients from different risk and ethnic groups between July 2007 and April 2011. Patients were designated as "high-risk" if their clinical history predicted a high prior probability, wherein LR testing was performed automatically in conjunction with sequencing. "Elective" patients did not meet the high-risk criteria, but underwent LR testing as ordered by the referring health care provider.

Results: Overall BRCA1/2 mutation prevalence among high-risk patients was 23.8% versus 8.2% for the elective group. The mutation profile for high-risk patients was 90.1% sequencing mutations versus 9.9% LRs, and for elective patients, 94.1% sequencing versus 5.9% LRs. This difference may reflect the bias in high-risk patients to carry mutations in BRCA1, which has a higher penetrance and frequency of LRs compared with BRCA2. There were significant differences in the prevalence and types of LRs in patients of different ancestries. LR mutations were significantly more common in Latin American/Caribbean patients.

Conclusions: Comprehensive LR testing in conjunction with full gene sequencing is an appropriate strategy for clinical BRCA1/2 analysis.

Figure 1

The spectrum of rearrangements detected in BRCA1 (breast cancer 1, early onset) and BRCA2 (breast cancer 2, early onset) across all patient samples tested during the given time frame are shown. The extents of large rearrangements relative to a 5′ to 3′ gene structure schematic are depicted. Note that both genes start at exon 1, but that BRCA1 has no exon 4. Blue bars represent deletions, red bars indicate duplications, and the green bar represents a documented triplication. Five recurrent BRCA1 rearrangements detected by the Large Rearrangement Panel are indicated with hashed bars. Rearrangements are indicated from the midpoint between affected exons for this schematic; actual breakpoint locations are not implied. Asterisk (*) denotes rearrangements that were observed 5 or more times in this time period.