Prediction of individual genetic risk to prostate cancer using a polygenic score
Year: 2015
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction. METHODS: We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. RESULTS: The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk. CONCLUSIONS: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.
Source: The Prostate
DOI: 10.1002/pros.23037
Authors: Robert Szulkin, Thomas Whitington, Martin Eklund, Markus Aly, Rosalind A. Eeles, Douglas Easton, ZSofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G. Giles, Melissa C. Southey, Liesel M. Fitzgerald, Brian E. Henderson, Fredrick Schumacher, Christopher A. Haiman, Johanna Schleutker, Tiina Wahlfors, Teuvo LJ Tammela, Børge G. Nordestgaard, Tim J. Key, Ruth C. Travis, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, Paul Pharoah, Nora Pashayan, Kay-Tee Khaw, Janet L. Stanford, Stephen N. Thibodeau, Shannon K. McDonnell, Daniel J. Schaid, Christiane Maier, Walther Vogel, Manuel Luedeke, Kathleen Herkommer, Adam S. Kibel, Cezary Cybulski, Jan Lubiński, Wojciech Kluźniak, Lisa Cannon-Albright, Hermann Brenner, Katja Butterbach, Christa Stegmaier, Jong Y. Park, Thomas Sellers, Hui-Yi Lim, Chavdar Slavov, Radka Kaneva, Vanio Mitev, Jyotsna Batra, Judith A. Clements, The Australian Prostate Cancer BioResource, Amanda Spurdle, Manuel R. Teixeira, Paula Paulo, Sofia Maia, Hardev Pandha, Agnieszka Michael, Andrzej Kierzek, Henrik Gronberg, Fredrik Wiklund
Institutions: Karolinska Institutet, Danderyds sjukhus, National Health Service, Royal Marsden NHS Foundation Trust, Institute of Cancer Research, University of Cambridge, University of Manchester, University of Warwick, The University of Melbourne, Cancer Council Victoria, University of Southern California, USC Norris Comprehensive Cancer Center, University of Turku, Tampere University, Fimlab (Finland), University of Tampere, Tampere University Hospital, University of Copenhagen, Herlev Hospital, Copenhagen University Hospital, University of Oxford, Cancer Research UK, Cancer Research UK Cambridge Center, Addenbrooke's Hospital, University of Bristol, John Radcliffe Hospital, University College London, University of Washington, Fred Hutch Cancer Center, Mayo Clinic, University Hospital Ulm, TUM Klinikum, Technical University of Munich, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Dana-Farber Brigham Cancer Center, International Hereditary Cancer Center, Pomeranian Medical University, University of Utah, George E. Wahlen Department of VA Medical Center, German Cancer Research Center, Deutsches Konsortium für Translationale Krebsforschung, Krebsregister Saarland, Moffitt Cancer Center, Alexandrovska Hospital, Medical University of Sofia, Queensland University of Technology, Australian Prostate Centre, QIMR Berghofer Medical Research Institute, Universidade do Porto, Instituto Português de Oncologia Francisco Gentil, IPO Porto, Instituto de Ciências Biomédicas Albel Salazar, University of Surrey
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: G1791794685, NIHR Senior Investigator Award, G2899816875, G4015216323, G5215675497, G5897142711, NIHR Senior Investigator Award, G6195211026, G6283257732, G651485119, G6723261869, G7378152860, G8473384893, University of Southern California Norris Comprehensive Cancer Center Support Grant (CCSG)
OpenAlex ID: W1509320938