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.

Characteristics of individuals with breast cancer rearrangements in BRCA1 and BRCA2

“…4,5,17 We were able to confirm these findings. More specifically BART-positive individuals were significantly more likely to be of Latin American/Caribbean ancestry compared with BART-negative individuals (paternal ancestry: OR 5 5.95, P 5 .0001; maternal ancestry: OR 5 4.14, P 5 .0003, respectively).…”

“…Most studies have shown that the prevalence of BART positivity is as low as 1% in unselected testers. Data from Myriad Genetic Laboratories show that in individuals meeting their criteria for automatic BART testing, the prevalence of BART mutations is 7.5%, 4 although the majority of them are included in the LRP. Furthermore, their data suggest that individuals of Latin American/Caribbean ancestry as well as Near East/Mideast ancestry have a higher prevalence of BART mutations (20.3% and 19.5%, respectively).…”

“…Furthermore, their data suggest that individuals of Latin American/Caribbean ancestry as well as Near East/Mideast ancestry have a higher prevalence of BART mutations (20.3% and 19.5%, respectively). 4 A recent publication from the City of Hope also suggested that individuals of Hispanic origin have a high prevalence of LR. 5 We assembled data from 6 centers in the United States on individuals who initially tested negative for the Comprehensive BRACAnalysis test and had BART testing.…”

Frequency of Rearrangements Versus Small Indels Mutations in BRCA1 and BRCA2 Genes in Turkish Patients with High Risk Breast and Ovarian Cancer

“…Most (25/27) rearrangements were found in patients with hereditary ovarian cancer (7). The rearrangement ratio (40.9%) given by Aktaş et al (7) for patients with ovarian cancer who had family histories was very high according to the international literature (4,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The second study investigated the rearrangement ratio in patients with hereditary breast cancer, but with a small sample size.…”

Founder and Recurrent Mutations in BRCA1 and BRCA2 Genes in Latin American Countries: State of the Art and Literature Review

“…The prevalence of rearrangement variants varies significantly in different populations [56]. Large genomic rearrangements may account for up 21.4% of the variants in high risk patients from Latin America and the Caribbean [57]. The development of clinically useful BRCA mutation panels will require a deep knowledge of the mutation spectrum and prevalence in each Latin American country.…”