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Multiple Novel Prostate Cancer Predisposition Loci Confirmed by an International Study: The PRACTICAL Consortium

¹ Section of Cancer Genetics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom; ² Cancer Research UK Genetic Epidemiology Unit, Strangeways Laboratory; ³ Surgical Oncology, Cambridge Research Institute, Cambridge, United Kingdom; ⁴ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center; Departments of ⁵ Epidemiology and ⁶ Biostatistics, School of Public Health and Community Medicine, University of Washington, Seattle, Washington; ⁷ National Human Genome Research Institute, NIH, Bethesda, Maryland; ⁸ Institute of Medical Technology, University of Tampere and Tampere University Hospital; ⁹ Department of Urology, Tampere University Hospital and Medical School, University of Tampere, Tampere, Finland; ¹⁰ Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California; ¹¹ Mayo Clinic, Rochester, Minnesota; ¹² Department of Gynecology and Obstetrics, ¹³ Gynaecology Research Unit, and ¹⁴ Department of Radiation Oncology, Hannover Medical School, Hannover, Germany; ¹⁵ Institute for Cancer Studies, University of Sheffield Medical School, Sheffield, United Kingdom; ¹⁶ Institut für Humangenetik; ¹⁷ Klinikum für Urologie und Kinderurologie, Universitätsklinikum Ulm, Germany; ¹⁸ University of Nottingham, Nottingham, United Kingdom; ¹⁹ Chulabhorn Cancer Research Centre, Bangkok, Thailand; ²⁰ School of Public Health and Institute of Health and Biomedical Innovation, Queensland University of Technology; ²¹ Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research; ²² Viertel Centre for Research in Cancer Control, The Cancer Council Queensland; ²³ University of Queensland, Department of Surgery, Royal Brisbane and Women's Hospital; ²⁴ School of Population Health, University of Queensland, Brisbane, Australia; ²⁵ Northern California Cancer Center, Fremont, California, and Stanford University School of Medicine, Stanford, California; ²⁶ Cancer Epidemiology Centre, The Cancer Council Victoria; ²⁷ Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Carlton, Australia; ²⁸ Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Australia; ²⁹ Division of Genetic Medicine and Division of Oncology, University Hospitals of Geneva, Geneva, Switzerland; ³⁰ Division of Medical Genetics, Institut Central des Hôpitaux Valaisans, Sion, Switzerland; and ³¹ Program in Cancer Genetics, and ³² Research Institute, McGill University Health Center, McGill University, Montreal, Quebec, Canada

Requests for reprints: Rosalind A. Eeles, Translational Cancer Genetics Team, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom. Phone: 44-20-8661-3642; Fax: 44-20-8770-1489. E-mail: Rosalind.Eeles{at}icr.ac.uk

A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10^–17). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2052–61)

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