Novel breast cancer susceptibility loci under linkage peaks identified in African ancestry consortia.
- Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, 270 Farber Hall, Buffalo, NY 14214, United States.
- Department of Preventive Population and Public Health Sciences, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, 1450 Biggy Street, Los Angeles, CA 90033, United States.
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, United States.
- Department of Internal Medicine, University of Utah School of Medicine, 30 North Mario Capecchi Dr, 3rd Floor North, Salt Lake City, UT 84112, United States.
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, Nashville, TN 37203, United States.
- Department of Molecular Physiology and Biophysics, Vanderbilt University, 707 Light Hall 2215 Garland Avenue, Nashville, TN 37232, United States.
- Department of Family and Community Medicine, Meharry Medical College, 1005 Dr. DB Todd Jr, Blvd. Nashville, TN 37208, United States.
- Department of Public Health Sciences, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, United States.
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, Bethesda, MD 20892, United States.
- Department of Biostatistics, Boston University, 715 Albany St, Boston, MA 02118, United States.
- Slone Epidemiology Center, Boston University, L-7, 72 East Concord Street, Boston, MA 02118, United States.
- Department of Epidemiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 135 Dauer Drive, CB 7435, Chapel Hill, NC 27599, United States.
- Department of Nutritional Sciences, University of Michigan School of Public Health, 1860 SPH I, 1415 Washington Heights, Ann Arbor, MI 48109, United States.
- Department of Epidemiology & Population Health, Stanford University School of Medicine, 3145 Porter Dr, Suite E223, MC 5393, Palo Alto, CA 94304, United States.
- Division of Biomarkers of Early Detection and Prevention Department of Population Sciences, Beckman Research Institute of the City of Hope, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, United States.
- Sylvester Comprehensive Cancer Center and Department of Public Health Sciences, University of Miami Miller School of Medicine, 1120 NW 14th St, CRB 1511, Miami, FL 33136, United States.
- Department of Radiology, School of Medicine, University of North Carolina at Chapel Hill, 130 Mason Farm Rd., Chapel Hill, NC 27599, United States.
- Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute of New Jersey, 120 Albany Street, Tower 2, 8th Floor, New Brunswick, NJ 08903, United States.
- Department of Pathology, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Ave., Los Angeles, CA 90033, United States.
- Genomics, Development and Disease Section, Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 31 Center Dr, Bethesda, MD 20894, United States.
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, United States.
- Department of Surgery, College of Medicine, University of Ibadan, Queen Elizabeth II Road, Ibadan, 200285, Nigeria.
- Center for Population and Reproductive Health, College of Medicine, University of Ibadan, UCH, Queen Elizabeth II Road, Ibadan, 200285, Nigeria.
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, 2 Worts Causeway, Cambridge, CB1 8RN, United Kingdom.
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, United Kingdom.
- Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Iroon Avenue 6, 2371 Ayius Dometios, Nicosia, Cyprus.
- Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, PO Box 12233, Research Triangle Park, NC 27709, United States.
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, PO Box 12233, Research Triangle Park, NC 27709, United States.
- Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD 20892, United States.
- Department of Medicine, Abramson Cancer Center, The Perelman School of Medicine at the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19140, United States.
- Chronic Disease Research Centre and Faculty of Medical Sciences, University of the West Indies, Jemmotts Lane, Avalon, Bridgetown, Barbados.
- Department of Family, Population and Preventive Medicine, Stony Brook University, 100 Nicolls Road, Stony Brook, NY 11794, United States.
- Laboratory of Human Carcinogenesis, National Cancer Institute, 37 Convent Drive, Bethesda, MD 20892, United States.
- College of Pharmacy, The Ohio State University, 217 Lloyd M. Parks Hall, 500 West 12th Ave., Columbus, OH 43210, United States.
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, 170 Rosenau Hall, CB #7400, 135 Dauer Drive, Chapel Hill, NC 27599, United States.
- Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago, 5841 S Maryland Avenue, Chicago, IL 60637, United States.
BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs.
METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG).
RESULTS: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16).
CONCLUSION: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.