Abstract A63: A strategy for more efficient BRCA analysis in an underserved Latina population

Background: Breast cancer (BC) is the most common cancer and the leading cause of cancer death in Latinas. Mutations in BRCA genes are associated with 5% of all BC and a larger proportion of young women with BC. Large rearrangements, not detectable by standard sequencing, account for up to 15% of deleterious BRCA mutations. The lifetime risk of developing BC associated with a BRCA mutation may be as high as 85%. We previously reported on the prevalence of deleterious BRCA mutations (31% of 110 families) in a Latino high-risk clinic population in Southern California, and also identified a unique recurrent large BRCA1 rearrangement (deletion of BRCA1 exons 9–12), likely of Mexican origin. BRCA1 185delAG was detected in independent Latino families, and through haplotyping we established that they shared a common ancestral origin with Jewish carrier families. We hypothesized that a panel of recurrent Latina BRCA mutations to pre-screen high risk patient samples will demonstrate clinical utility and reduce genotyping cost. Methods: Using a new high-throughput Sequenom® platform, we developed a prototype multiplex panel to test for recurrent BRCA mutations, including 185delAG, and a 3-primer assay to test for the BRCA1 rearrangement mutation. We created a clinical protocol and procedure that enabled sample collection, DNA extraction, amplification and mutation panel analysis on the Sequenom platform within a 72 hour time frame. We piloted this 18 mutation panel in the clinical genetic cancer risk assessment setting. Positive assays were confirmed in a CLIA-approved laboratory by sequencing of the specific segment, and comprehensive BRCA sequencing was performed on all samples with negative results. We applied the panel prospectively in a pilot study of 23 consecutive Latina breast cancer patients referred to the City of Hope Cancer Screening & Prevention Program Network for genetic cancer risk assessment. Results: A substantial proportion (4/7, 57%) of deleterious BRCA mutations were detected by the panel in this proof of principle pilot study in our high risk clinic, suggesting strong translational potential. All 4 mutations were confirmed by commercial sequencing. The majority of these patients were from an underserved/uninsured clinic, and the pre-screening procedure (with an estimated panel assay cost of $5/sample, and $250 for reconfirmation of detected mutations by the CLIA-certified commercial laboratory) saved an estimated $6,600 over the alternative of complete sequencing (representing a 15% savings on the budget for genotyping all 23 patients). Conclusions: Our data suggest that the development of and testing for a panel of recurrent BRCA mutations in high risk Latina populations will reduce testing cost and enable more women to benefit from limited resources. Knowledge about the genetic etiology of breast cancer in Latinas will facilitate screening and cancer prevention.