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Polygenic Risk Modelling for Prediction of Epithelial Ovarian Cancer Risk

By Eileen O Dareng, Jonathan Tyrer, Daniel R. Barnes, Michelle R Jones, Xin Yang, Katja K.H. Aben, Muriel A Adank, Simona A Agata, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Gerasimos Aravantinos, Banu K. Arun, Annelie Augustinsson, Judith Balmaña, Elisa V. Bandera, Rosa B. Barkardottir, Daniel Barrowdale, Matthias W. Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, Marina Bermisheva, Marcus Q Bernardini, Line Bjorge, Amanda Black, Natalia V. Bogdanova, Bernardo Bonanni, Ake Borg, James Brenton, Agnieszka Budzilowska, Ralf Butzow, Saundra S. Buys, Hui Cai, Maria A. Caligo, Ian Campbell, Rikki Cannioto, Hayley Cassingham, Jenny Chang-Claude, Stephen J. Chanock, Kexin Chen, Yoke-Eng Chiew, Wendy K. Chung, Kathleen B.M. Claes, Sarah Colanna, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, Linda S. Cook, Fergus J. Couch, Mary B. Daly, Fanny Dao, Eleanor Davies, Miguel de la Hoya, Robin de Putter, Allison DePersia, Peter Devilee, Orland Diez, Yuan Chun Ding, Jennifer A Doherty, Susan M. Domchek, Thilo Dörk, Andreas du Bois, Matthias Dürst, Diana M Eccles, Heather A Eliassen, Christoph Engel, D.Gareth Evans, Peter Fasching, James M. Flanagan, Lenka Foretova, Renée T. Fortner, Eitan Friedman, Patricia A. Ganz, Judy Garber, Francesca Gensini, Graham G Giles, Gord Glendon, Andrew K. Godwin, Marc T. Goodman, Mark H. Greene, Jacek Gronwald, OPAL Study Group, AOCS Group, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Thomas V.O Hansen, Holly R. Harris, Mikael Hartman, Florian Heitz, Michelle A.T. Hildebrandt, Estrid Høgdall, Claus K. Høgdall, John L Hopper, Ruea-Yea Huang, Chad Huff, Peter J. Hulick, David G. Huntsman, Evgeny N. Imyanitov, KConFab Investigators, HEBON Investigators, Claudine Isaacs, Anna Anna Jakubowska, Paul James, Ramunas Janavicius, Allan Jensen, Oskar Th Johannsson, Esther M. John, Michael Jones, Daehee Kang, Beth Y Karlan, Anthony Karnezis, Linda E. Kelemen, Elza Khusnutdinova, Lambertus A Kiemeney, Byoung-Gie Kim, Susanne K. Kjaer, Iam Komenaka, Jolanta Kupryjanczyk, Allison W. Kurian, Ava Kwong, Diether Lambrechts, Melissa C Larson, Conxi Lazaro, Nhu D. Le, Goska Leslie, Jenny Lester, Fabienne Lesueur, Douglas Levine, Lian Li, Jingmei Li, Jennifer T. Loud, Karen H. Lu, Jan Lubiński, Eva Machackova, Phuong L Mai, Siranoush Manoukian, Jeffrey Marks, Rayna Kim Matsuno, Keitaro Matsuo, Taymaa May, Lesley McGuffog, John R McLaughlin, Iain A. McNeish, Noura Mebirouk, Usha Menon, Austin Miller, Roger L. Milne, Albina Minlikeeva, Francesmary Modugno, Marco Montagna, Kirsten B. Moysich, Elizabeth Munro, Katherine L Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Joanne Ngeow Yuen Yie, Henriette Roed Nielsen, Finn C. Nielsen, Liene Nikitina-Zake, Kunle Odunsi, Kenneth Offit, Edith Olah, Siel Olbrecht, Olufunmilayo I. Olopade, Sara H. Olson, Håkan Olsson, Ana Osorio, Laura Papi, Sue K Park, Michael T. Parsons, Harsha Pathak, Inge S Pedersen, Ana Peixoto, Tanja Pejovic, Pedro Perez-Segura, Jenny B. Permuth, Beth Peshkin, Paolo Peterlongo, Anna Piskorz, Darya Prokofyeva, Paolo Radice, Johanna Rantala, Marjorie Riggan, Harvey B Risch, Cristina Rodriguez-Antona, Eric A. Ross, Mary Anne Rossing, Ingo Runnebaum, Dale P Sandler, Marta Santamariña, Penny Soucy, Rita K. Schmutzler, V.Wendy Setiawan, Kang Shan, Weiva Sieh, Jacques Simard, Christian F. Singer, Anna Sokolenko, Honglin Song, Melissa Southey, Helen Steed, Dominique Stoppa-Lyonnet, Rebecca Sutphen, Anthony J. Swerdlow, Yen Yen Tan, Manuel Teixeira, Soo Hwang Teo, Kathryn L Terry, Mary Beth Terry, Mads Thomassen, Pamela J. Thompson, Liv Cecilie Thomsen, Darcy L Hull, Marc Tischkowitz, Linda Titus, Amanda Toland, Diana Torres, Britton Trabert, Ruth Travis, Nadine Tung, Shelley S Tworoger, Ellen Valen, Anne M. van Altena, Annemieke H van der Hout, Els Van Nieuwenhuysen, Elizabeth J. van Rensburg, Ana Vega, Digna Velez Edwards, Robert A. Vierkant, Frances Wang, Barbara Wappenschmidt, Penelope M Webb, Clarice R. Weinberg, Jeffrey N. Weitzel, Nicolas Wentzensen, Emily White, Alice S. Whittemore, Stacey J Winham, Alicja Wolk, Yin-Ling Woo, Anna H. Wu, Li Yan, Drakoulis Yannoukakos, Katia M Zavaglia, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Douglas Easton, Kate Lawrenson, Anna deFazio, Thomas A Sellers, Susan J. Ramus, Celeste Pearce, Alvaro N Montiero, Julie M. Cunningham, Ellen L Goode, Joellen M. Schildkraut, Andrew Berchuck, Georgia Chenevix-Trench, Simon A Gayther, Antonis C. Antoniou, Paul DP. Pharoah

Posted 02 Dec 2020
medRxiv DOI: 10.1101/2020.11.30.20219220

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28-1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08-1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30-1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

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