Nine genes for inherited predisposition to breast cancer among African-American women. O. I. Olopade1, T. Walsh2, Y. Zheng1, S. Casadei2, A. M. Thornton2, M. K. Lee2, M. Churpek1, D. Huo1, C. Zvosec1, F. Liu1, Q. Niu1, J. Zhang1, J. Fackenthal1, M.-C. King2, J. E. Churpek1 1) Dept Medicine, Univ Chicago, Chicago, IL; 2) Division of Medical Genetics, Univ Washington, Seattle, WA.

   African American (AA) women are more likely to develop early onset and triple negative breast cancer than are white women. One potential contributor to these disparities may be more inherited mutations among AA women in breast cancer susceptibility genes. However, the magnitude of this effect is not known because the frequency and spectrum of inherited mutations in BRCA1 and BRCA2 among AA women is not well characterized. Even less is known among about the frequency and spectrum of inherited mutations in other breast cancer genes among AA women. We addressed this question using BROCA, a targeted genomic capture assay, to screen all 26 known breast cancer genes in DNA from AA women with breast cancer. BROCA detects all classes of mutations: point mutations, small insertions and deletions, and large genomic rearrangements (CNVs). For this project, we counted only unambiguously damaging mutations: truncations, complete gene deletions, splice mutations shown experimentally to lead to a mutant message, and missenses shown experimentally to lead to loss of protein function. All candidate variants were validated by Sanger sequencing. Participants in the project were 395 unrelated AA women with breast cancer ascertained through the Cancer Risk Clinic at The University of Chicago. Of the participants, 18% (71/395) carried one or more damaging mutations in nine different breast cancer genes. Mutation frequencies were: 28 in BRCA1, 30 in BRCA2, 3 in CHEK2, 3 in PALB2, 4 in ATM, 2 in BARD1, 2 in PTEN, 1 in TP53, and 1 in BRIP1. Three patients carried 2 mutations each. The 74 events involved 57 different mutations, 3 of which were large genomic deletions. Preliminary analysis indicates that the prevalence of damaging mutations was more than 25% among patients diagnosed at age 45 or younger, or with a close relative with either breast or ovarian cancer, or with triple negative breast cancer, or with two breast cancer primaries. Given that participants expressed interest in genetic testing, the prevalence of damaging mutations in this series is likely higher than among AA patients generally. Nonetheless, the unexpectedly high frequency in this population of damaging mutations in BRCA1, BRCA2, and other genes indicate that comprehensive genetic testing should be recommended and supported by health insurance for all breast cancer patients meeting National Comprehensive Cancer Network (NCCN) guidelines and for relatives of patients with damaging mutations.

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