title: Implications of polygenic risk for personalised colorectal cancer screening.
abstract: BACKGROUND
  We modelled the utility of applying a personalised screening approach for colorectal cancer (CRC) when compared with standard age-based screening. In this personalised screening approach, eligibility is determined by absolute risk which is calculated from age and polygenic risk score (PRS), where the PRS is relative risk attributable to common genetic variation. In contrast, eligibility in age-based screening is determined only by age.
  
  
  METHODS
  We calculated absolute risks of CRC from UK population age structure, incidence and mortality rate data, and a PRS distribution which we derived for the 37 known CRC susceptibility variants. We compared the number of CRC cases potentially detectable by personalised and age-based screening. Using Genome-Wide Complex Trait Analysis to calculate the heritability attributable to common variation, we repeated the analysis assuming all common CRC risk variants were known.
  
  
  RESULTS
  Based on the known CRC variants, individuals with a PRS in the top 1% have a 2.9-fold increased CRC risk over the population median. Compared with age-based screening (aged 60: 10-year absolute risk 1.96% in men, 1.19% in women, as per the UK NHS National Bowel Screening Programme), personalised screening of individuals aged 55-69 at the same risk would lead to 16% fewer men and 17% fewer women being eligible for screening with 10% and 8%, respectively, fewer screen-detected cases. If all susceptibility variants were known, individuals with a PRS in the top 1% would have an estimated 7.7-fold increased risk. Personalised screening would then result in 26% fewer men and women being eligible for screening with 7% and 5% fewer screen-detected cases.
  
  
  CONCLUSIONS
  Personalised screening using PRS has the potential to optimise population screening for CRC and to define those likely to maximally benefit from chemoprevention. There are however significant technical and operational details to be addressed before any such programme is introduced.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London.
authors.forename: M J E
authors.initials: MJ
authors.lastname: Frampton
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London.
authors.forename: P
authors.initials: P
authors.lastname: Law
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London.
authors.forename: K
authors.initials: K
authors.lastname: Litchfield
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds.
authors.forename: E J
authors.initials: EJ
authors.lastname: Morris
authors.affiliation: Oxford Cancer Centre, Department of Oncology, University of Oxford, Churchill Hospital, Oxford.
authors.forename: D
authors.initials: D
authors.lastname: Kerr
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London William Harvey Research Institute, Queen Mary University London, London.
authors.forename: C
authors.initials: C
authors.lastname: Turnbull
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: I P
authors.initials: IP
authors.lastname: Tomlinson
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London richard.houlston@icr.ac.uk.
authors.forename: R S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D000368:Aged; D015179:Colorectal Neoplasms / Q000175:diagnosis*; D055088:Early Detection of Cancer / Q000379:methods*; D004739:England; D005260:Female; D006801:Humans; D008297:Male; D008403:Mass Screening / Q000379:methods*; D008875:Middle Aged; D057285:Precision Medicine / Q000379:methods*; D012306:Risk; D012307:Risk Factors
keywords: colorectal cancer; personalised screening; polygenic risk