Polygenic risk modeling for prediction of epithelial ovarian cancer risk
Authors: Dareng Eileen O. , Tyrer Jonathan P. , Barnes Daniel R. , Jones Michelle R. , Yang Xin , Aben Katja K. H. , Adank Muriel A. , Agata Simona , Andrulis Irene L. , Anton-Culver Hoda , Antonenkova Natalia N. , Aravantinos Gerasimos , Arun Banu K. , Augustinsson Annelie , Balmaña Judith , Bandera Elisa V. , Barkardottir Rosa B. , Barrowdale Daniel , Beckmann Matthias W. , Beeghly-Fadiel Alicia , Benitez Javier , Bermisheva Marina , Bernardini Marcus Q. , Bjorge Line , Black Amanda , Bogdanova Natalia V. , Bonanni Bernardo , Borg Ake , Brenton James D. , Budzilowska Agnieszka , Butzow Ralf , Buys Saundra S. , Cai Hui , Caligo Maria A. , Campbell Ian , Cannioto Rikki , Cassingham Hayley , Chang-Claude Jenny , Chanock Stephen J. , Chen Kexin , Chiew Yoke-Eng , Chung Wendy K. , Claes Kathleen B. M. , Colonna Sarah ,   GEMO Study Collaborators, Lesueur Fabienne , Mebirouk Noura ,   GC-HBOC Study Collaborators, Engel Christoph , Schmutzler Rita K. ,   EMBRACE Collaborators, Barrowdale Daniel , Davies Eleanor , Eccles Diana M. , Evans D. Gareth , Cook Linda S. , Couch Fergus J. , Daly Mary B. , Dao Fanny , Davies Eleanor , de la Hoya Miguel , de Putter Robin , Dennis Joe , DePersia Allison , Devilee Peter , Diez Orland , Ding Yuan Chun , Doherty Jennifer A. , Domchek Susan M. , Dörk Thilo , du Bois Andreas , Dürst Matthias , Eccles Diana M. , Eliassen Heather A. , Engel Christoph , Evans Gareth D. , Fasching Peter A. , Flanagan James M. , Fortner Renée T. , Machackova Eva , Friedman Eitan , Ganz Patricia A. , Garber Judy , Gensini Francesca , Giles Graham G. , Glendon Gord , Godwin Andrew K. , Goodman Marc T. , Greene Mark H. , Gronwald Jacek ,   OPAL Study Group,   AOCS Group, Hahnen Eric , Haiman Christopher A. , Håkansson Niclas , Hamann Ute , Hansen Thomas V. O. , Harris Holly R. , Hartman Mikael , Heitz Florian , Hildebrandt Michelle A. T. , Høgdall Estrid , Høgdall Claus K. , Hopper John L. , Huang Ruea-Yea , Huff Chad , Hulick Peter J. , Huntsman David G. , Imyanitov Evgeny N. ,   KConFab Investigators, Chenevix-Trench Georgia ,   HEBON Investigators, Adank Muriel A. , Devilee Peter , van der Hout Annemieke H. , Isaacs Claudine , Jakubowska Anna , James Paul A. , Janavicius Ramunas , Jensen Allan , Johannsson Oskar Th. , John Esther M. , Jones Michael E. , Kang Daehee , Karlan Beth Y. , Karnezis Anthony , Kelemen Linda E. , Khusnutdinova Elza , Kiemeney Lambertus A. , Kim Byoung-Gie , Kjaer Susanne K. , Komenaka Ian , Kupryjanczyk Jolanta , Kurian Allison W. , Kwong Ava , Lambrechts Diether , Larson Melissa C. , Lazaro Conxi , Le Nhu D. , Leslie Goska , Lester Jenny , Lesueur Fabienne , Levine Douglas A. , Li Lian , Li Jingmei , Loud Jennifer T. , Lu Karen H. , Lubiński Jan , Mai Phuong L. , Manoukian Siranoush , Marks Jeffrey R. , Matsuno Rayna Kim , Matsuo Keitaro , May Taymaa , McGuffog Lesley , McLaughlin John R. , McNeish Iain A. , Mebirouk Noura , Menon Usha , Miller Austin , Milne Roger L. , Minlikeeva Albina , Modugno Francesmary , Montagna Marco , Moysich Kirsten B. , Munro Elizabeth , Nathanson Katherine L. , Neuhausen Susan L. , Nevanlinna Heli , Yie Joanne Ngeow Yuen , Nielsen Henriette Roed , Nielsen Finn C. , Nikitina-Zake Liene , Odunsi Kunle , Offit Kenneth , Olah Edith , Olbrecht Siel , Olopade Olufunmilayo I. , Olson Sara H. , Olsson Håkan , Osorio Ana , Papi Laura , Park Sue K. , Parsons Michael T. , Pathak Harsha , Pedersen Inge Sokilde , Peixoto Ana , Pejovic Tanja , Perez-Segura Pedro , Permuth Jennifer B. , Peshkin Beth , Peterlongo Paolo , Piskorz Anna , Prokofyeva Darya , Radice Paolo , Rantala Johanna , Riggan Marjorie J. , Risch Harvey A. , Rodriguez-Antona Cristina , Ross Eric , Rossing Mary Anne , Runnebaum Ingo , Sandler Dale P. , Santamariña Marta , Soucy Penny , Schmutzler Rita K. , Setiawan V. Wendy , Shan Kang , Sieh Weiva , Simard Jacques , Singer Christian F. , Sokolenko Anna P. , Song Honglin , Southey Melissa C. , Steed Helen , Stoppa-Lyonnet Dominique , Sutphen Rebecca , Swerdlow Anthony J. , Tan Yen Yen , Teixeira Manuel R. , Teo Soo Hwang , Terry Kathryn L. , Terry Mary Beth ,   The OCAC Consortium, Dareng Eileen O. , Tyrer Jonathan P. , Jones Michelle R. , Aben Katja K. H. , Anton-Culver Hoda , Antonenkova Natalia N. , Aravantinos Gerasimos , Beckmann Matthias W. , Beeghly-Fadiel Alicia , Benitez Javier , Bermisheva Marina , Bernardini Marcus Q. , Bjorge Line , Bogdanova Natalia V. , Brenton James D. , Budzilowska Agnieszka , Butzow Ralf , Cai Hui , Campbell Ian , Cannioto Rikki , Chang-Claude Jenny , Chanock Stephen J. , Chen Kexin , Chiew Yoke-Eng , Cook Linda S. , Dao Fanny , Dennis Joe , Doherty Jennifer A. , Dörk Thilo , du Bois Andreas , Dürst Matthias , Eccles Diana M. , Eliassen Heather A. , Fasching Peter A. , Flanagan James M. , Fortner Renée T. , Giles Graham G. , Goodman Marc T. , Gronwald Jacek , Haiman Christopher A. , Håkansson Niclas , Harris Holly R. , Heitz Florian , Hildebrandt Michelle A. T. , Høgdall Estrid , Høgdall Claus K. , Huang Ruea-Yea , Huff Chad , Huntsman David G. , Jakubowska Anna , Jensen Allan , Jones Michael E. , Kang Daehee , Karlan Beth Y. , Karnezis Anthony , Kelemen Linda E. , Khusnutdinova Elza , Kiemeney Lambertus A. , Kim Byoung-Gie , Kjaer Susanne K. , Kupryjanczyk Jolanta , Lambrechts Diether , Larson Melissa C. , Le Nhu D. , Lester Jenny , Levine Douglas A. , Lu Karen H. , Lubiński Jan , Marks Jeffrey R. , Matsuno Rayna Kim , Matsuo Keitaro , May Taymaa , McLaughlin John R. , McNeish Iain A. , Milne Roger L. , Minlikeeva Albina , Modugno Francesmary , Moysich Kirsten B. , Munro Elizabeth , Nevanlinna Heli , Odunsi Kunle , Olbrecht Siel , Olson Sara H. , Olsson Håkan , Osorio Ana , Park Sue K. , Pejovic Tanja , Permuth Jennifer B. , Piskorz Anna , Prokofyeva Darya , Riggan Marjorie J. , Risch Harvey A. , Rodriguez-Antona Cristina , Rossing Mary Anne , Runnebaum Ingo , Sandler Dale P. , Setiawan V. Wendy , Shan Kang , Sieh Weiva , Song Honglin , Southey Melissa C. , Steed Helen , Sutphen Rebecca , Swerdlow Anthony J. , Teo Soo Hwang , Terry Kathryn L. , Thompson Pamela J. , Thomsen Liv Cecilie Vestrheim , Titus Linda , Trabert Britton , Travis Ruth , Tworoger Shelley S. , Valen Ellen , van Altena Anne M. , Van Nieuwenhuysen Els , Edwards Digna Velez , Vierkant Robert A. , Wang Frances , Webb Penelope M. , Weinberg Clarice R. , Wentzensen Nicolas , White Emily , Whittemore Alice S. , Winham Stacey J. , Wolk Alicja , Woo Yin-Ling , Wu Anna H. , Yan Li , Yannoukakos Drakoulis , Zheng Wei , Ziogas Argyrios , Lawrenson Kate , deFazio Anna , Ramus Susan J. , Pearce Celeste L. , Monteiro Alvaro N. , Cunningham Julie M. , Goode Ellen L. , Schildkraut Joellen M. , Berchuck Andrew , Gayther Simon A. , Pharoah Paul D. P. ,   The CIMBA Consortium, Barnes Daniel R. , Yang Xin , Adank Muriel A. , Agata Simona , Andrulis Irene L. , Arun Banu K. , Augustinsson Annelie , Balmaña Judith , Barkardottir Rosa B. , Barrowdale Daniel , Bonanni Bernardo , Borg Ake , Buys Saundra S. , Caligo Maria A. , Cassingham Hayley , Chung Wendy K. , Claes Kathleen B. M. , Colonna Sarah , Couch Fergus J. , Daly Mary B. , Davies Eleanor , de la Hoya Miguel , de Putter Robin , DePersia Allison , Devilee Peter , Diez Orland , Ding Yuan Chun , Domchek Susan M. , Eccles Diana M. , Engel Christoph , Evans D. Gareth , Machackova Eva , Friedman Eitan , Ganz Patricia A. , Garber Judy , Gensini Francesca , Glendon Gord , Godwin Andrew K. , Greene Mark H. , Hahnen Eric , Hamann Ute , Hansen Thomas V. O. , Hartman Mikael , Hopper John L. , Hulick Peter J. , Imyanitov Evgeny N. , Isaacs Claudine , James Paul A. , Janavicius Ramunas , Johannsson Oskar Th. , John Esther M. , Komenaka Ian , Kurian Allison W. , Kwong Ava , Lazaro Conxi , Leslie Goska , Lesueur Fabienne , Li Jingmei , Loud Jennifer T. , Mai Phuong L. , Manoukian Siranoush , McGuffog Lesley , Mebirouk Noura , Miller Austin , Montagna Marco , Nathanson Katherine L. , Neuhausen Susan L. , Yie Joanne Ngeow Yuen , Nielsen Henriette Roed , Nikitina-Zake Liene , Offit Kenneth , Olah Edith , Olopade Olufunmilayo I. , Papi Laura , Parsons Michael T. , Pathak Harsha , Pedersen Inge Sokilde , Peixoto Ana , Perez-Segura Pedro , Peshkin Beth , Peterlongo Paolo , Radice Paolo , Rantala Johanna , Ross Eric , Santamariña Marta , Soucy Penny , Schmutzler Rita K. , Simard Jacques , Singer Christian F. , Sokolenko Anna P. , Stoppa-Lyonnet Dominique , Tan Yen Yen , Teixeira Manuel R. , Terry Mary Beth , Thomassen Mads , Thull Darcy L. , Tischkowitz Marc , Toland Amanda E. , Torres Diana , Tung Nadine , van der Hout Annemieke H. , van Rensburg Elizabeth J. , Vega Ana , Wappenschmidt Barbara , Weitzel Jeffrey N. , Zavaglia Katia M. , Zorn Kristin K. , Sellers Thomas A. , Chenevix-Trench Georgia , Antoniou Antonis C. , Thomassen Mads , Thompson Pamela J. , Thomsen Liv Cecilie Vestrheim , Thull Darcy L. , Tischkowitz Marc , Titus Linda , Toland Amanda E. , Torres Diana , Trabert Britton , Travis Ruth , Tung Nadine , Tworoger Shelley S. , Valen Ellen , van Altena Anne M. , van der Hout Annemieke H. , Van Nieuwenhuysen Els , van Rensburg Elizabeth J. , Vega Ana , Edwards Digna Velez , Vierkant Robert A. , Wang Frances , Wappenschmidt Barbara , Webb Penelope M. , Weinberg Clarice R. , Weitzel Jeffrey N. , Wentzensen Nicolas , White Emily , Whittemore Alice S. , Winham Stacey J. , Wolk Alicja , Woo Yin-Ling , Wu Anna H. , Yan Li , Yannoukakos Drakoulis , Zavaglia Katia M. , Zheng Wei , Ziogas Argyrios , Zorn Kristin K. , Kleibl Zdenek , Easton Douglas , Lawrenson Kate , DeFazio Anna , Sellers Thomas A. , Ramus Susan J. , Pearce Celeste L. , Monteiro Alvaro N. , Cunningham Julie , Goode Ellen L. , Schildkraut Joellen M. , Berchuck Andrew , Chenevix-Trench Georgia , Gayther Simon A. , Antoniou Antonis C. , Pharoah Paul D. P. 
Published: January 2022

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 ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. 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 ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, 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.