Polygenic risk scores for prediction of breast cancer and breast cancer subtypes Journal Article


Authors: Mavaddat, N.; Michailidou, K.; Dennis, J.; Lush, M.; Fachal, L.; Lee, A.; Tyrer, J. P.; Chen, T. H.; Wang, Q.; Bolla, M. K.; Yang, X.; Adank, M. A.; Ahearn, T.; Aittomäki, K.; Allen, J.; Andrulis, I. L.; Anton-Culver, H.; Antonenkova, N. N.; Arndt, V.; Aronson, K. J.; Auer, P. L.; Auvinen, P.; Barrdahl, M.; Beane Freeman, L. E.; Beckmann, M. W.; Behrens, S.; Benitez, J.; Bermisheva, M.; Bernstein, L.; Blomqvist, C.; Bogdanova, N. V.; Bojesen, S. E.; Bonanni, B.; Børresen-Dale, A. L.; Brauch, H.; Bremer, M.; Brenner, H.; Brentnall, A.; Brock, I. W.; Brooks-Wilson, A.; Brucker, S. Y.; Brüning, T.; Burwinkel, B.; Campa, D.; Carter, B. D.; Castelao, J. E.; Chanock, S. J.; Chlebowski, R.; Christiansen, H.; Clarke, C. L.; Collée, J. M.; Cordina-Duverger, E.; Cornelissen, S.; Couch, F. J.; Cox, A.; Cross, S. S.; Czene, K.; Daly, M. B.; Devilee, P.; Dörk, T.; dos-Santos-Silva, I.; Dumont, M.; Durcan, L.; Dwek, M.; Eccles, D. M.; Ekici, A. B.; Eliassen, A. H.; Ellberg, C.; Engel, C.; Eriksson, M.; Evans, D. G.; Fasching, P. A.; Figueroa, J.; Fletcher, O.; Flyger, H.; Försti, A.; Fritschi, L.; Gabrielson, M.; Gago-Dominguez, M.; Gapstur, S. M.; García-Sáenz, J. A.; Gaudet, M. M.; Georgoulias, V.; Giles, G. G.; Gilyazova, I. R.; Glendon, G.; Goldberg, M. S.; Goldgar, D. E.; González-Neira, A.; Grenaker Alnæs, G. I.; Grip, M.; Gronwald, J.; Grundy, A.; Guénel, P.; Haeberle, L.; Hahnen, E.; Haiman, C. A.; Håkansson, N.; Hamann, U.; Hankinson, S. E.; Harkness, E. F.; Hart, S. N.; He, W.; Hein, A.; Heyworth, J.; Hillemanns, P.; Hollestelle, A.; Hooning, M. J.; Hoover, R. N.; Hopper, J. L.; Howell, A.; Huang, G.; Humphreys, K.; Hunter, D. J.; Jakimovska, M.; Jakubowska, A.; Janni, W.; John, E. M.; Johnson, N.; Jones, M. E.; Jukkola-Vuorinen, A.; Jung, A.; Kaaks, R.; Kaczmarek, K.; Kataja, V.; Keeman, R.; Kerin, M. J.; Khusnutdinova, E.; Kiiski, J. I.; Knight, J. A.; Ko, Y. D.; Kosma, V. M.; Koutros, S.; Kristensen, V. N.; Krüger, U.; Kühl, T.; Lambrechts, D.; Le Marchand, L.; Lee, E.; Lejbkowicz, F.; Lilyquist, J.; Lindblom, A.; Lindström, S.; Lissowska, J.; Lo, W. Y.; Loibl, S.; Long, J.; Lubiński, J.; Lux, M. P.; MacInnis, R. J.; Maishman, T.; Makalic, E.; Maleva Kostovska, I.; Mannermaa, A.; Manoukian, S.; Margolin, S.; Martens, J. W. M.; Martinez, M. E.; Mavroudis, D.; McLean, C.; Meindl, A.; Menon, U.; Middha, P.; Miller, N.; Moreno, F.; Mulligan, A. M.; Mulot, C.; Muñoz-Garzon, V. M.; Neuhausen, S. L.; Nevanlinna, H.; Neven, P.; Newman, W. G.; Nielsen, S. F.; Nordestgaard, B. G.; Norman, A.; Offit, K.; Olson, J. E.; Olsson, H.; Orr, N.; Pankratz, V. S.; Park-Simon, T. W.; Perez, J. I. A.; Pérez-Barrios, C.; Peterlongo, P.; Peto, J.; Pinchev, M.; Plaseska-Karanfilska, D.; Polley, E. C.; Prentice, R.; Presneau, N.; Prokofyeva, D.; Purrington, K.; Pylkäs, K.; Rack, B.; Radice, P.; Rau-Murthy, R.; Rennert, G.; Rennert, H. S.; Rhenius, V.; Robson, M.; Romero, A.; Ruddy, K. J.; Ruebner, M.; Saloustros, E.; Sandler, D. P.; Sawyer, E. J.; Schmidt, D. F.; Schmutzler, R. K.; Schneeweiss, A.; Schoemaker, M. J.; Schumacher, F.; Schürmann, P.; Schwentner, L.; Scott, C.; Scott, R. J.; Seynaeve, C.; Shah, M.; Sherman, M. E.; Shrubsole, M. J.; Shu, X. O.; Slager, S.; Smeets, A.; Sohn, C.; Soucy, P.; Southey, M. C.; Spinelli, J. J.; Stegmaier, C.; Stone, J.; Swerdlow, A. J.; Tamimi, R. M.; Tapper, W. J.; Taylor, J. A.; Terry, M. B.; Thöne, K.; Tollenaar, R. A. E. M.; Tomlinson, I.; Truong, T.; Tzardi, M.; Ulmer, H. U.; Untch, M.; Vachon, C. M.; van Veen, E. M.; Vijai, J.; Weinberg, C. R.; Wendt, C.; Whittemore, A. S.; Wildiers, H.; Willett, W.; Winqvist, R.; Wolk, A.; Yang, X. R.; Yannoukakos, D.; Zhang, Y.; Zheng, W.; Ziogas, A.; ABCTB Investigators; kConFab/AOCS Investigators; NBCS Collaborators; Dunning, A. M.; Thompson, D. J.; Chenevix-Trench, G.; Chang-Claude, J.; Schmidt, M. K.; Hall, P.; Milne, R. L.; Pharoah, P. D. P.; Antoniou, A. C.; Chatterjee, N.; Kraft, P.; García-Closas, M.; Simard, J.; Easton, D. F.
Article Title: Polygenic risk scores for prediction of breast cancer and breast cancer subtypes
Abstract: Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57–1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628–0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs. © 2018 The Authors
Keywords: breast; prediction; risk; screening; epidemiology; stratification; genetic; score; polygenic; cancer
Journal Title: American Journal of Human Genetics
Volume: 104
Issue: 1
ISSN: 0002-9297
Publisher: Cell Press  
Date Published: 2019-01-03
Start Page: 21
End Page: 34
Language: English
DOI: 10.1016/j.ajhg.2018.11.002
PUBMED: 30554720
PROVIDER: scopus
PMCID: PMC6323553
DOI/URL:
Notes: Vijai Joseph's first and last names are reversed on the original publication -- Article -- Export Date: 1 February 2019 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Kenneth Offit
    496 Offit
  2. Mark E Robson
    358 Robson
  3. Vijai Joseph
    113 Joseph