Addressing health disparities in Hispanic breast cancer: accurate and inexpensive sequencing of BRCA1 and BRCA2

Abstract

Background: Germline mutations in the BRCA1 and BRCA2 genes account for 20-25 % of inherited breast cancers and about 10 % of all breast cancer cases. Detection of BRCA mutation carriers can lead to therapeutic interventions such as mastectomy, oophorectomy, hormonal prevention therapy, improved screening, and targeted therapies such as PARP-inhibition. We estimate that African Americans and Hispanics are 4-5 times less likely to receive BRCA screening, despite having similar mutation frequencies as non-Jewish Caucasians, who have higher breast cancer mortality. To begin addressing this health disparity, we initiated a nationwide trial of BRCA testing of Latin American women with breast cancer. Patients were recruited through community organizations, clinics, public events, and by mail and Internet. Subjects completed the consent process and questionnaire, and provided a saliva sample by mail or in person. DNA from 120 subjects was used to sequence the entirety of BRCA1 and BRCA2 coding regions and splice sites, and validate pathogenic mutations, with a total material cost of $85/subject. Subjects ranged in age from 23 to 81 years (mean age, 51 years), 6 % had bilateral disease, 57 % were ER/PR+, 23 % HER2+, and 17 % had triple-negative disease.

Results: A total of seven different predicted deleterious mutations were identified, one newly described and the rest rare. In addition, four variants of unknown effect were found.

Conclusions: Application of this strategy on a larger scale could lead to improved cancer care of minority and underserved populations.

Keywords: Breast cancer; Genetic testing; Health disparity; Hispanic populations; Underserved populations.

Figures

Fig. 1

BRCA screening by ethnicity. The numbers of Western European (West Eur) women, Latin American (Latin Am), and African American (African) women who received BRCA screening per 100,000 population between 2006 and 2008, covered by Hall et al. [17] is displayed (see Table 1 for details)

Fig. 2

Selected BRCA2 mutations. The Ion Torrent data displayed in IGV [51] is shown for the newly described 6005delT mutation in the left panel, a. The display shows individual forward (F) sequence reads in red and reverse (R) reads in blue. The 6005delT mutation can be seen as a gap in the sequence (arrow) in approximately half of the F and R reads – this is consistent with a heterozygous mutation. Sanger sequencing (not shown) confirmed this mutation. b. Both the Ion Torrent (above) and Sanger sequence (displayed in Mutation Explorer, SoftGenetics, below) for the C1787S and G1788D mutations are displayed in the right panel. The co-occurrence of the C1787S and G1788D variants on the same allele can be clearly seen in the Ion Torrent reads, whereas phase cannot be determined from the Sanger traces. Note: BRCA1 is in reverse orientation in the genome, and so IGV display is of the reverse complement

Fig. 3

Screenshots of selected variants. a, A region with multiple homopolymers in BRCA1 is shown, sequenced by the two enzyme formulations. b. A missense variant (benign) that was not called with the standard enzyme, but was by Hi-Q