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PLoS Genet. 2014 Feb 13;10(2):e1004129. doi: 10.1371/journal.pgen.1004129. eCollection 2014.

Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.

Author information

  • 1The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
  • 2Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
  • 3Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Cambridge, United Kingdom.
  • 4Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Addenbrooke's Hospital, Cambridge and Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom.
  • 5Nuffield Department of Surgical Sciences, University of Oxford, Oxford, and Faculty of Medical Science, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
  • 6School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
  • 7Cancer Epidemiology Centre, The Cancer Council Victoria, Carlton, Victoria, Australia and Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Melbourne, Victoria, Australia.
  • 8Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, United States of America.
  • 9Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
  • 10Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, United States of America.
  • 11Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, United States of America.
  • 12Nutritional Epidemiology Branch, National Cancer Institute, NIH, EPS-3044, Bethesda, Maryland, United States of America.
  • 13Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri, United States of America.
  • 14Department of Medic Biochemistry and Genetics, University of Turku, Turku and Institute of Biomedical Technology and BioMediTech, University of Tampere and FimLab Laboratories, Tampere, Finland.
  • 15Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
  • 16Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 17Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 18Department of Epidemiology & Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
  • 19Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
  • 20Cancer Prevention Institute of California, Fremont, California, United States of America, and Stanford University School of Medicine, Stanford, California, United States of America.
  • 21Division of Epidemiology, Department of Population Health, NYU Langone Medical Center, NYU Cancer Institute, New York, New York, United States of America.
  • 22Clinical Gerontology Unit, University of Cambridge, Cambridge, United Kingdom.
  • 23Department of Epidemiology, School of Public Health, University of Washington and Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
  • 24National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
  • 25International Epidemiology Institute, Rockville, Maryland, and Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
  • 26Mayo Clinic, Rochester, Minnesota, United States of America.
  • 27Department of Urology, University Hospital Ulm and Institute of Human Genetics University Hospital Ulm, Ulm, Germany.
  • 28Division of Urologic Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
  • 29International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
  • 30Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine and George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah, United States of America.
  • 31Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 32Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, Florida, United States of America.
  • 33Molecular Medicine Center and Department of Medical Chemistry and Biochemistry, Medical University - Sofia, Sofia, Bulgaria.
  • 34Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Queensland, Australia.
  • 35Biomedical Sciences Institute (ICBAS), Porto University, Porto, and Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
  • 36Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America.
  • 37Warwick Medical School, University of Warwick, Coventry, United Kingdom.

Abstract

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

PMID:
24550738
[PubMed - indexed for MEDLINE]
PMCID:
PMC3923678
Free PMC Article
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