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Cancer Epidemiol Biomarkers Prev. 2014 Apr;23(4):658-69. doi: 10.1158/1055-9965.EPI-13-0340. Epub 2014 Feb 3.

A genome-wide association study of early-onset breast cancer identifies PFKM as a novel breast cancer gene and supports a common genetic spectrum for breast cancer at any age.

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Authors' Affiliations: Center for Cancer Epidemiology and Prevention; Departments of Health Studies, Medicine, and Human Genetics; Comprehensive Cancer Center, University of Chicago, Chicago, Illinois; Department of Health Research and Policy, Stanford University School of Medicine; Stanford Cancer Institute, Stanford; Cancer Prevention Institute of California, Fremont; Department of Preventive Medicine, University of Southern California, Los Angeles; Stanford Cancer Institute, Palo Alto, California; Epidemiology and Genetics Research Program; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York; Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix; Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, Arizona; Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts; Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg; Clinic of Gynaecology and Obstetrics, Division for Gynaecological Tumor-Genetics, Technische Universität München; Max Planck Institute of Psychiatry, Munich; Department of Obstetrics and Gynaecology, Division of Molecular Gynaeco-Oncology, PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne; Foundation for Quality and Efficiency in Health Care, Cologne; Department of Cancer Epidemiology/Clinical Cancer Registry; Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg; Department of Psychiatry, University of Mainz, Mainz, Germany; Samuel Lunenfeld Research Institute; Zane Cohen Cen


Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10(-4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer.

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