Integration of targeted BRCA1/BRCA2 mutation screening and genetic ancestry in an African-American breast cancer cohort from South Florida.

A53 Background : Disparities in breast cancer stage of presentation, prognosis and mortality in women of African ancestry (AA) are well documented. Recent evidence from our laboratory (as well as others) suggests that certain BRCA1/BRCA2 mutations and variants appear to be either at increased frequency (or specific) to AA women at-risk for breast cancer (BC).
 Methods : To further evaluate the frequency of these variants, we analyzed a cohort of 113 AA BC patients ascertained from South Florida using an AA targeted mutation screening panel which detects 37 BRCA1 and 22 BRCA2 mutations/ unclassified variants (UCVs), respectively. These mutations and UCVs were selected for study based on previous detection in our laboratory, or/and as a result of a thorough literature review. In addition, 100 ancestry informative markers (AIMs) distributed across the genome were used to estimate genetic ancestry of each patient and of this cohort. Average allele frequency difference for these AIMs was 70% between west African and European populations. Individual genetic ancestry was estimated for each sample from the genotype data using the Bayesian Markov Chain-Monte Carlo (MCMC) method implemented in the program STRUCTURE 2.1. STRUCTURE 2.1 was run under the admixture model using prior population information and independent allele frequencies. We chose the MCMC method using K=2 parental populations and a burn-in length of 30,000 for 70,000 repetitions.
 Results: The patient cohort was comprised of 31 patients with a family history and 77 patients without. 47 or 61% of the patients were self-reported African-American; 23.3% were self-reported Haitian, and 11.7% were self-reported Jamaican. This cohort was skewed towards early-onset breast cancer - 35.7% of the AA patients and 44% of the Haitian and Jamaican BC patients had onset BRCA1/ BRCA2 recurrent mutations/UCVs and % ancestry. For example, N119D, a BRCA2 missense mutation/UCV detected in 9.5% of the BC patients, was detected 80% of the time in individuals with > 88% West African ancestry. Another example is S1140G, a BRCA1 missense mutation/UCV detected in 3.4% of the BC patients, was detected almost exclusively in patients with extremely high West African ancestry (>90%). Our long-term plan is to apply the technologies used in this pilot study to a large multi-ethnic case: control study, in order to gain new information regarding frequencies and conferred risks of selected BRCA1 / BRCA2 mutations and variants in the context of genetic ancestry.
 The mutation screening panel has been granted preliminary patent protection through the University of Miami Office of Technology Transfer.