M J E Frampton1, P Law1, K Litchfield1, E J Morris2, D Kerr3, C Turnbull4, I P Tomlinson5, R S Houlston6. 1. Division of Genetics and Epidemiology, The Institute of Cancer Research, London. 2. Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds. 3. Oxford Cancer Centre, Department of Oncology, University of Oxford, Churchill Hospital, Oxford. 4. Division of Genetics and Epidemiology, The Institute of Cancer Research, London William Harvey Research Institute, Queen Mary University London, London. 5. Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. 6. Division of Genetics and Epidemiology, The Institute of Cancer Research, London richard.houlston@icr.ac.uk.
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. DESIGN: 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. CONCLUSION: 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.
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. DESIGN: 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. CONCLUSION: 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: Catherine L Saunders; Britt Kilian; Deborah J Thompson; Luke J McGeoch; Simon J Griffin; Antonis C Antoniou; Jon D Emery; Fiona M Walter; Joe Dennis; Xin Yang; Juliet A Usher-Smith Journal: Cancer Prev Res (Phila) Date: 2020-02-18
Authors: Luke McGeoch; Catherine L Saunders; Simon J Griffin; Jon D Emery; Fiona M Walter; Deborah J Thompson; Antonis C Antoniou; Juliet A Usher-Smith Journal: Cancer Epidemiol Biomarkers Prev Date: 2019-07-10 Impact factor: 4.254
Authors: Dayna R Cenin; Steffie K Naber; Anne C de Weerdt; Mark A Jenkins; David B Preen; Hooi C Ee; Peter C O'Leary; Iris Lansdorp-Vogelaar Journal: Cancer Epidemiol Biomarkers Prev Date: 2019-11-20 Impact factor: 4.254
Authors: Malene Djursby; Thomas van Overeem Hansen; Karin A W Wadt; Majbritt Busk Madsen; Lukas Adrian Berchtold; Charlotte Kvist Lautrup; Sara Markholt; Uffe Birk Jensen; Lotte Nylandsted Krogh; Malene Lundsgaard; Anne Marie Gerdes; Mef Nilbert; Christina Therkildsen Journal: Hum Genet Date: 2022-07-29 Impact factor: 5.881
Authors: Tomas Tanskanen; Linda van den Berg; Niko Välimäki; Mervi Aavikko; Eivind Ness-Jensen; Kristian Hveem; Yvonne Wettergren; Elinor Bexe Lindskog; Neeme Tõnisson; Andres Metspalu; Kaisa Silander; Giulia Orlando; Philip J Law; Sari Tuupanen; Alexandra E Gylfe; Ulrika A Hänninen; Tatiana Cajuso; Johanna Kondelin; Antti-Pekka Sarin; Eero Pukkala; Pekka Jousilahti; Veikko Salomaa; Samuli Ripatti; Aarno Palotie; Heikki Järvinen; Laura Renkonen-Sinisalo; Anna Lepistö; Jan Böhm; Jukka-Pekka Mecklin; Nada A Al-Tassan; Claire Palles; Lynn Martin; Ella Barclay; Albert Tenesa; Susan M Farrington; Maria N Timofeeva; Brian F Meyer; Salma M Wakil; Harry Campbell; Christopher G Smith; Shelley Idziaszczyk; Tim S Maughan; Richard Kaplan; Rachel Kerr; David Kerr; Daniel D Buchanan; Aung K Win; John Hopper; Mark A Jenkins; Polly A Newcomb; Steve Gallinger; David Conti; Fredrick R Schumacher; Graham Casey; Jeremy P Cheadle; Malcolm G Dunlop; Ian P Tomlinson; Richard S Houlston; Kimmo Palin; Lauri A Aaltonen Journal: Int J Cancer Date: 2017-10-12 Impact factor: 7.396
Authors: Mark A Jenkins; Aung K Win; James G Dowty; Robert J MacInnis; Enes Makalic; Daniel F Schmidt; Gillian S Dite; Mirosl Kapuscinski; Mark Clendenning; Christophe Rosty; Ingrid M Winship; Jon D Emery; Sibel Saya; Finlay A Macrae; Dennis J Ahnen; David Duggan; Jane C Figueiredo; Noralane M Lindor; Robert W Haile; John D Potter; Michelle Cotterchio; Steven Gallinger; Polly A Newcomb; Daniel D Buchanan; Graham Casey; John L Hopper Journal: Fam Cancer Date: 2019-10 Impact factor: 2.375