title: Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis.
abstract: OBJECTIVE
  This study aimed to quantify the probability of overdiagnosis of prostate cancer by polygenic risk.
  
  
  METHODS
  We calculated the polygenic risk score based on 66 known prostate cancer susceptibility variants for 17,012 men aged 50-69 years (9,404 men identified with prostate cancer and 7,608 with no cancer) derived from three UK-based ongoing studies. We derived the probabilities of overdiagnosis by quartiles of polygenic risk considering that the observed prevalence of screen-detected prostate cancer is a combination of underlying incidence, mean sojourn time (MST), test sensitivity, and overdiagnosis.
  
  
  RESULTS
  Polygenic risk quartiles 1 to 4 comprised 9, 18, 25, and 48% of the cases, respectively. For a prostate-specific antigen test sensitivity of 80% and MST of 9 years, 43, 30, 25, and 19% of the prevalent screen-detected cancers in quartiles 1 to 4, respectively, were likely to be overdiagnosed cancers. Overdiagnosis decreased with increasing polygenic risk, with 56% decrease between the lowest and the highest polygenic risk quartiles.
  
  
  CONCLUSIONS
  Targeting screening to men at higher polygenic risk could reduce the problem of overdiagnosis and lead to a better benefit-to-harm balance in screening for prostate cancer.
authors.affiliation: Department of Applied Health Research, University College London, London, UK.
authors.forename: Nora
authors.initials: N
authors.lastname: Pashayan
authors.affiliation: Centre for Cancer Prevention, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Duffy
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
authors.forename: David E
authors.identifier: http://orcid.org/0000-0002-6033-5086
authors.initials: DE
authors.lastname: Neal
authors.affiliation: Nuffield Department of Surgery, Oxford John Radcliffe Hospital, University of Oxford, Headington, Oxford, UK.
authors.forename: Freddie C
authors.initials: FC
authors.lastname: Hamdy
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Donovan
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Martin
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Harrington
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Benlloch
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Ali
authors.initials: A
authors.lastname: Amin Al Olama
authors.affiliation: Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Mitul
authors.initials: M
authors.lastname: Shah
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Kote-Jarai
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research & Royal Marsden NHS Foundation Trust, London, UK.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Eeles
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Paul D
authors.identifier: http://orcid.org/0000-0001-8494-732X
authors.initials: PD
authors.lastname: Pharoah
mesh_terms: D000368:Aged; D000465:Algorithms; D014408:Biomarkers, Tumor; D055088:Early Detection of Cancer / Q000379:methods / Q000592:standards; D056426:Genetic Loci; D005820:Genetic Testing / Q000379:methods / Q000592:standards; D006801:Humans; D008297:Male; D000069342:Medical Overuse; D008875:Middle Aged; D008957:Models, Genetic; D015233:Models, Statistical; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D012306:Risk; D012680:Sensitivity and Specificity; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D014408:Biomarkers, Tumor