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Carcinogenesis. 2016 Sep;37(9):870-877. doi: 10.1093/carcin/bgw067. Epub 2016 Jun 7.

An exome-wide analysis of low frequency and rare variants in relation to risk of breast cancer in African American Women: the AMBER Consortium.

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Department of Preventive Medicine , Keck School of Medicine , University of Southern California/Norris Comprehensive Cancer Center , Los Angeles, CA 90033 , USA.
Department of Cancer Prevention and Control , Roswell Park Cancer Institute , Buffalo, NY 14263 , USA.
Department of Epidemiology , Gillings School of Global Public Health , University of North Carolina at Chapel Hill , Chapel Hill , NC 27599 , USA.
Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute , Buffalo, NY 14263 , USA.
Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey , New Brunswick, NJ 08903 , USA and.
Department of Biostatistics, Boston University School of Public Health , Boston, MA 02118 , USA.


A large percentage of breast cancer heritability remains unaccounted for, and most of the known susceptibility loci have been established in European and Asian populations. Rare variants may contribute to the unexplained heritability of this disease, including in women of African ancestry (AA). We conducted an exome-wide analysis of rare variants in relation to risk of overall and subtype-specific breast cancer in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, which includes data from four large studies of AA women. Genotyping on the Illumina Human Exome Beadchip yielded data for 170 812 SNPs and 8287 subjects: 3629 cases (1093 estrogen receptor negative (ER-), 1968 ER+, 568 ER unknown) and 4658 controls, the largest exome chip study to date for AA breast cancer. Pooled gene-based association analyses were performed using the unified optimal sequence kernel association test (SKAT-O) for variants with minor allele frequency (MAF) ≤ 5%. In addition, each variant with MAF >0.5% was tested for association using logistic regression. There were no significant associations with overall breast cancer. However, a novel gene, FBXL22 (P = 8.2×10(-6)), and a gene previously identified in GWAS of European ancestry populations, PDE4D (P = 1.2×10(-6)), were significantly associated with ER- breast cancer after correction for multiple testing. Cases with the associated rare variants were also negative for progesterone and human epidermal growth factor receptors-thus, triple-negative cancer. Replication is required to confirm these gene-level associations, which are based on very small counts at extremely rare SNPs.

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