Genome-wide association of familial prostate cancer cases identifies evidence for a rare segregating haplotype at 8q24.21.

Previous genome-wide association studies (GWAS) of prostate cancer risk focused on cases unselected for family history and have reported over 100 significant associations. The International Consortium for Prostate Cancer Genetics (ICPCG) has now performed a GWAS of 2511 (unrelated) familial prostate cancer cases and 1382 unaffected controls from 12 member sites. All samples were genotyped on the Illumina 5M+exome single nucleotide polymorphism (SNP) platform. The GWAS identified a significant evidence for association for SNPs in six regions previously associated with prostate cancer in population-based cohorts, including 3q26.2, 6q25.3, 8q24.21, 10q11.23, 11q13.3, and 17q12. Of note, SNP rs138042437 (p = 1.7e(-8)) at 8q24.21 achieved a large estimated effect size in this cohort (odds ratio = 13.3). 116 previously sampled affected relatives of 62 risk-allele carriers from the GWAS cohort were genotyped for this SNP, identifying 78 additional affected carriers in 62 pedigrees. A test for an excess number of affected carriers among relatives exhibited strong evidence for co-segregation of the variant with disease (p = 8.5e(-11)). The majority (92 %) of risk-allele carriers at rs138042437 had a consistent estimated haplotype spanning approximately 100 kb of 8q24.21 that contained the minor alleles of three rare SNPs (dosage minor allele frequencies <1.7 %), rs183373024 (PRNCR1), previously associated SNP rs188140481, and rs138042437 (CASC19). Strong evidence for co-segregation of a SNP on the haplotype further characterizes the haplotype as a prostate cancer predisposition locus.

Human genetics. 2016 Jun 04 [Epub ahead of print]

Craig C Teerlink, Daniel Leongamornlert, Tokhir Dadaev, Alun Thomas, James Farnham, Robert A Stephenson, Shaun Riska, Shannon K McDonnell, Daniel J Schaid, William J Catalona, S Lilly Zheng, Kathleen A Cooney, Anna M Ray, Kimberly A Zuhlke, Ethan M Lange, Graham G Giles, Melissa C Southey, Liesel M Fitzgerald, Antje Rinckleb, Manuel Luedeke, Christiane Maier, Janet L Stanford, Elaine A Ostrander, Elina M Kaikkonen, Csilla Sipeky, Teuvo Tammela, Johanna Schleutker, Kathleen E Wiley, Sarah D Isaacs, Patrick C Walsh, William B Isaacs, Jianfeng Xu, Geraldine Cancel-Tassin, Olivier Cussenot, Diptasri Mandal, Cecelia Laurie, Cathy Laurie, PRACTICAL consortium , International Consortium for Prostate Cancer Genetics , Stephen N Thibodeau, Rosalind A Eeles, Zsofia Kote-Jarai, Lisa Cannon-Albright

Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84108, USA. ., Division of Genetics and Epidemiology, Institute of Cancer Research, London, SW7 3RP, UK., Division of Genetics and Epidemiology, Institute of Cancer Research, London, SW7 3RP, UK., Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84108, USA., Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84108, USA., Department of Urology, University of Utah School of Medicine, Salt Lake City, UT, 84132, USA., Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA., Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA., Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA., Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA., Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA., Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA., Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, 3004, Australia., Department of Pathology, University of Melbourne, Melbourne, 3010, Australia., Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, 3004, Australia., Department of Urology, University Hospital Ulm, 53179, Ulm, Germany., Department of Urology, University Hospital Ulm, 53179, Ulm, Germany., Institute for Human Genetics, University of Ulm, 89081, Ulm, Germany., Division of Public Health Sciences, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA, 98109, USA., Cancer Genetics Branch, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD, 20892, USA., Department of Medical Biochemistry and Genetics, University of Turku, 20520, Turku, Finland., Department of Medical Biochemistry and Genetics, University of Turku, 20520, Turku, Finland., Department of Urology, University of Tampere and Tampere University Hospital, 33520, Tampere, Finland., Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, 20520, Turku, Finland., Brady Urological Institute, Johns Hopkins University, Baltimore, MD, 21287, USA., Brady Urological Institute, Johns Hopkins University, Baltimore, MD, 21287, USA., Brady Urological Institute, Johns Hopkins University, Baltimore, MD, 21287, USA., Brady Urological Institute, Johns Hopkins University, Baltimore, MD, 21287, USA., Program for Personalized Cancer Care, NorthShore University Health System, Evanston, IL, 60201, USA., CeRePP, Hopital Tenon, Assistance Publique-Hopitaux de Paris, 75020, Paris, France., CeRePP, Hopital Tenon, Assistance Publique-Hopitaux de Paris, 75020, Paris, France., Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA., Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA., Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA., Department of Lab Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA., Division of Genetics and Epidemiology, Institute of Cancer Research, London, SW7 3RP, UK., Division of Genetics and Epidemiology, Institute of Cancer Research, London, SW7 3RP, UK., Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84108, USA.

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