Hormone-related pathways and risk of breast cancer subtypes in African American women
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We sought to investigate genetic variation in hormone pathways in relation to risk of overall and subtype-specific breast cancer in women of African ancestry (AA). Genotyping and imputation yielded data on 143,934 SNPs in 308 hormone-related genes for 3663 breast cancer cases (1098 ER−, 1983 ER+, 582 ER unknown) and 4687 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. AMBER includes data from four large studies of AA women: the Carolina Breast Cancer Study, the Women’s Circle of Health Study, the Black Women’s Health Study, and the Multiethnic Cohort Study. Pathway- and gene-based analyses were conducted, and single-SNP tests were run for the top genes. There were no strong associations at the pathway level. The most significantly associated genes were GHRH, CALM2, CETP, and AKR1C1 for overall breast cancer (gene-based nominal p ≤ 0.01); NR0B1, IGF2R, CALM2, CYP1B1, and GRB2 for ER+ breast cancer (p ≤ 0.02); and PGR, MAPK3, MAP3K1, and LHCGR for ER− disease (p ≤ 0.02). Single-SNP tests for SNPs with pairwise linkage disequilibrium r 2 < 0.8 in the top genes identified 12 common SNPs (in CALM2, CETP, NR0B1, IGF2R, CYP1B1, PGR, MAPK3, and MAP3K1) associated with overall or subtype-specific breast cancer after gene-level correction for multiple testing. Rs11571215 in PGR (progesterone receptor) was the SNP most strongly associated with ER− disease. We identified eight genes in hormone pathways that contain common variants associated with breast cancer in AA women after gene-level correction for multiple testing.
KeywordsBreast cancer Genetics Pathways Hormones African Americans
We thank participants and staff of the contributing studies. We wish also to acknowledge the late Robert Millikan, DVM, MPH, PhD, who was instrumental in the creation of this consortium. Pathology data were obtained from numerous state cancer registries (Arizona, California, Colorado, Connecticut, Delaware, District of Columbia, Florida, Georgia, Hawaii, Illinois, Indiana, Kentucky, Louisiana, Maryland, Massachusetts, Michigan, New Jersey, New York, North Carolina, Oklahoma, Pennsylvania, South Carolina, Tennessee, Texas, Virginia). The results reported do not necessarily represent their views or the views of the NIH.
This work was supported by the National Institutes of Health (NIH) P01 CA151135 to C.B. Ambrosone, A.F. Olshan, and J.R. Palmer; NIH R01 CA098663 to J.R. Palmer; NIH R01 CA058420 and UM1 CA164974 to L. Rosenberg; NIH R01 CA100598 to C.B. Ambrosone and E.V. Bandera; NIH UM1 CA164973 and RO1 CA54281 to L.N. Kolonel; NIH P50 CA58223 to C. Perou; the U.S. Department of Defense Breast Cancer Research Program, Era of Hope Scholar Award Program grant W81XWH-08-1-0383 to C.A. Haiman; and the University Cancer Research Fund of North Carolina.
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no conflict of interest.
Informed consent was obtained from all individual participants included in this study.
Research involving human participants
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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