Abstract
Multiple prostate cancer (PCa) risk-related loci have been discovered by genome-wide association studies (GWAS) based on case–control designs. However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer (HPC). The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1,979 hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics, with a total of 5,730 affected men. The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 (regions 1, 2 and 3), 10q11, 11q13, 17q12 (region 1), 17q24 and Xp11. In subgroup analyses, three loci, at 8q24 (regions 1 and 2) plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 (region 2), 11q13, 17q12 (region 1), 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65 years or less. Our results indicate that at least a subset of PCa risk-related loci identified by case–control GWAS are also associated with disease risk in HPC families.
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Acknowledgment
We would like to express our gratitude to the many families who participated in the studies involved in the International Consortium for Prostate Cancer Genetics (ICPCG). The ICPCG, including the consortium’s Data Coordinating Center (DCC), is made possible by a grant from the National Institutes of Health U01 CA89600 (to William B. Isaacs). Additional support to participating groups, or members within groups, is as follows: University of Utah Group: The authors appreciate the support of the University of Utah Huntsman Cancer Institute (to Lisa A. Cannon-Albright). FHCRC/NHGRI Group: Partial support was provided by the Fred Hutchinson Cancer Research Center (to Janet L. Stanford) and National Human Genome Research Institute (to Elaine A. Ostrander). ACTANE Group: We appreciate the support of the CR-UK grant A8385 and the NIHR to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust (to Ros Eeles), and Cancer Research UK (to Doug Easton). University of Umeå Group: Partial support was provided by the Swedish Cancer Society and a Spear grant from the Umeå University Hospital, Umeå, Sweden (to Henrik Grönberg). University of Tampere Group: We appreciate the support of the Competitive Research Funding of the Pirkanmaa Hospital District (9L091), Reino Lahtikari Foundation, Finnish Cancer Organisations, Sigrid Juselius Foundation and Academy of Finland (116437 and 126714) (to Johanna Schleutker). Northwestern University Group: Partial support was provided from Robert H. Lurie Comprehensive Cancer Center and the Urological Research Foundation (to William J. Catalona). University of Michigan Group: Partial support was provided by NIH P50 CA69568, NIH R01 CA79596 (to Kathleen Cooney), and the University of Michigan Comprehensive Cancer Center. Data Coordinating Center: Partial support was provided by NCI CA119069 and CA129684 (to Jianfeng Xu). We also thank other investigators who contributed to this work: ACTANE Group: Daniel Leongamornlert, Ed Saunders, Malgorzata Tymrakiewicz, Lynne O’Brien, Emma Sawyer, Rosemary Wilkinson, and Stephen Edwards from The Institute of Cancer Research, Sutton, Surrey. University of Ulm Group: Manuel Luedeke and Mark Schrader from Department of Urology, University of Ulm, Germany; Josef Hoegel and Christian Kubisch from Institute of Human Genetics, University of Ulm, Germany; and Kathleen Herkommer from Department of Urology, Technical University of Munich, Germany.
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G. Jin and L. Lu contributed equally to this work.
K.A. Cooney, A.M. Ray, K.A. Zuhlke and E.M. Lange are the members of the University of Michigan ICPCG Group.
L.M. FitzGerald and J.L. Stanford are the members of the FHCRC/NHGRI ICPCG Group.
W.D. Foulkes, G.G. Giles, J.L. Hopper, G. Severi, R. Eeles, D. Easton, Z. Kote-Jarai, and M. Guy are the members of the ACTANE Consortium ICPCG Group.
A. Rinckleb, C. Maier and W. Vogel are the members of the University of Ulm ICPCG Group.
S.N. Thibodeau, S.K. McDonnell and D.J. Schaid are the members of the Mayo Clinic ICPCG Group.
F. Wiklund, H. Grönberg and M. Emanuelsson are the members of the University of Umeå ICPCG Group.
A.S. Whittemore, I. Oakley-Girvan and C.-L. Hsieh are the members of the BC/CA/HI ICPCG Group.
T. Wahlfors, T. Tammela and J. Schleutker are the members of the University of Tampere ICPCG Group.
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Jin, G., Lu, L., Cooney, K.A. et al. Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis: evidence from the International Consortium for Prostate Cancer Genetics (ICPCG). Hum Genet 131, 1095–1103 (2012). https://doi.org/10.1007/s00439-011-1136-0
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DOI: https://doi.org/10.1007/s00439-011-1136-0