title: Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers.
abstract: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates.
  
  
  
  We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS.
  
  
  
  The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P =  8.2×10 -53 ). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P =  7.2×10 -20 ). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS.
  
  
  
  BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.|Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Karoline B
authors.initials: KB
authors.lastname: Kuchenbaecker
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Lesley
authors.initials: L
authors.lastname: McGuffog
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Barrowdale
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lee
authors.affiliation: Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, Quebec, Canada.
authors.forename: Penny
authors.initials: P
authors.lastname: Soucy
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Joe
authors.initials: J
authors.lastname: Dennis
authors.affiliation: Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Domchek
authors.affiliation: Clinical Genetics, Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Robson
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
authors.affiliation: School of Women's and Children's Health, University of New South Wales, Australia; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst NSW 2010, Australia.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Ramus
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Nasim
authors.initials: N
authors.lastname: Mavaddat
authors.affiliation: Department of Epidemiology, Columbia University, New York, NY, USA.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Terry
authors.affiliation: Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Neuhausen
authors.affiliation: Center for Hereditary Breast and Ovarian Cancer and Center for Integrated Oncology, Medical Faculty, University Hospital Cologne, Germany.
authors.forename: Rita Katharina
authors.initials: RK
authors.lastname: Schmutzler
authors.affiliation: Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, Quebec, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Simard
authors.affiliation: Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Paul D P
authors.initials: PDP
authors.lastname: Pharoah
authors.affiliation: Clinical Genetics Research Laboratory, Department of Medicine, Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.affiliation: Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.affiliation: Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Antonis C
authors.initials: AC
authors.lastname: Antoniou
mesh_terms: D000293:Adolescent; D000328:Adult; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D020412:Multifactorial Inheritance; D009154:Mutation; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000378:metabolism; D018570:Risk Assessment / Q000379:methods / Q000706:statistics & numerical data; D012307:Risk Factors; D055815:Young Adult
chemical_list: D011960:Receptors, Estrogen