title: Prostate cancer (PCa) risk variants and risk of fatal PCa in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.
abstract: BACKGROUND
  Screening and diagnosis of prostate cancer (PCa) is hampered by an inability to predict who has the potential to develop fatal disease and who has indolent cancer. Studies have identified multiple genetic risk loci for PCa incidence, but it is unknown whether they could be used as biomarkers for PCa-specific mortality (PCSM).
  
  
  OBJECTIVE
  To examine the association of 47 established PCa risk single-nucleotide polymorphisms (SNPs) with PCSM.
  
  
  METHODS
  We included 10 487 men who had PCa and 11 024 controls, with a median follow-up of 8.3 yr, during which 1053 PCa deaths occurred.
  
  
  METHODS
  The main outcome was PCSM. The risk allele was defined as the allele associated with an increased risk for PCa in the literature. We used Cox proportional hazards regression to calculate the hazard ratios of each SNP with time to progression to PCSM after diagnosis. We also used logistic regression to calculate odds ratios for each risk SNP, comparing fatal PCa cases to controls.
  
  
  CONCLUSIONS
  Among the cases, we found that 8 of the 47 SNPs were significantly associated (p<0.05) with time to PCSM. The risk allele of rs11672691 (intergenic) was associated with an increased risk for PCSM, while 7 SNPs had risk alleles inversely associated (rs13385191 [C2orf43], rs17021918 [PDLIM5], rs10486567 [JAZF1], rs6465657 [LMTK2], rs7127900 (intergenic), rs2735839 [KLK3], rs10993994 [MSMB], rs13385191 [C2orf43]). In the case-control analysis, 22 SNPs were associated (p<0.05) with the risk of fatal PCa, but most did not differentiate between fatal and nonfatal PCa. Rs11672691 and rs10993994 were associated with both fatal and nonfatal PCa, while rs6465657, rs7127900, rs2735839, and rs13385191 were associated with nonfatal PCa only.
  
  
  CONCLUSIONS
  Eight established risk loci were associated with progression to PCSM after diagnosis. Twenty-two SNPs were associated with fatal PCa incidence, but most did not differentiate between fatal and nonfatal PCa. The relatively small magnitudes of the associations do not translate well into risk prediction, but these findings merit further follow-up, because they may yield important clues about the complex biology of fatal PCa.
  
  
  RESULTS
  In this report, we assessed whether established PCa risk variants could predict PCSM. We found eight risk variants associated with PCSM: One predicted an increased risk of PCSM, while seven were associated with decreased risk. Larger studies that focus on fatal PCa are needed to identify more markers that could aid prediction.
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA. Electronic address: ishui@hsph.harvard.edu.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Shui
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Lindström
authors.affiliation: Department of Surgery, Division of Urology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Kibel
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.affiliation: Genomic Epidemiology Group, German Cancer Research Center (Deutsches Krebsforschungszentrum), Heidelberg, Germany.
authors.forename: Daniele
authors.initials: D
authors.lastname: Campa
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Gerke
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Penney
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medicine, Baltimore, MD, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Berg
authors.affiliation: National Institute for Public Health and the Environment, Bilthoven, The Netherlands; Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands; School of Public Health, Imperial College London, London, United Kingdom.
authors.forename: H Bas
authors.initials: HB
authors.lastname: Bueno-de-Mesquita
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA; Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Gaithersburg, MD, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.affiliation: Urologic Oncology, University of Colorado, Denver, CO, USA.
authors.forename: E David
authors.initials: ED
authors.lastname: Crawford
authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
authors.forename: W Ryan
authors.initials: WR
authors.lastname: Diver
authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Gapstur
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Division of Aging, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Gaziano
authors.affiliation: Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Henderson
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hoover
authors.affiliation: International Agency for Research on Cancer, Lyon, France; Department of Biobank Research, Umeå University, Umeå, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Johansson
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Epidemiology, Murcia Regional Health Authority, Murcia, Spain; Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarro
authors.affiliation: Department of Public Health, Aarhus University, Aarhus, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Overvad
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Fredrick R
authors.initials: FR
authors.lastname: Schumacher
authors.affiliation: Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia; HuGeF Foundation, Torino, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Severi
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London, United Kingdom.
authors.forename: Afshan
authors.initials: A
authors.lastname: Siddiq
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Meir
authors.initials: M
authors.lastname: Stampfer
authors.affiliation: Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Stevens
authors.affiliation: Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Travis
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA; Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece; Hellenic Health Foundation, Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trichopoulos
authors.affiliation: HuGeF Foundation, Torino, Italy; School of Public Health, Imperial College London, London, United Kingdom.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA; Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Gaithersburg, MD, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
mesh_terms: D000368:Aged; D000483:Alleles; D001315:Australia / Q000453:epidemiology; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D005060:Europe / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality*; D012042:Registries; D018570:Risk Assessment; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor
keywords: Genetic epidemiology; Prostate cancer; Prostate cancer mortality; Risk single nucleotide polymorphisms