Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Polygenic risk modeling for prediction of epithelial ovarian cancer risk

European Journal of Human Genetics

10.1038/s41431-021-00987-7

http://dx.doi.org/10.1038/s41431-021-00987-7

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

Genetics (clinical), genetics

14 January 2022

Dareng, E. O., Tyrer, J. P., Barnes, D. R., Jones, M. R., Yang, X., Aben, K. K. H., Adank, M. A., Agata, S., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Aravantinos, G., Arun, B. K., Augustinsson, A., Balmaña, J., Bandera, E. V., Barkardottir, R. B., Barrowdale, D., … Beckmann, M. W. (2022). Polygenic risk modeling for prediction of epithelial ovarian cancer risk. European Journal of Human Genetics. https://doi.org/10.1038/s41431-021-00987-7

AbstractPolygenic 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.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the National Research Foundation - Singapore Fellowship
Grant Reference no. : NRF-NRFF2017-02

This research / project is supported by the National University Singapore (NUS) - Start-up Grant
Grant Reference no. : N.A

This research / project is supported by the National University Cancer Institute Singapore (NCIS) - Centre Grant
Grant Reference no. : NMRC/CG/NCIS/2010

This research / project is supported by the National University Cancer Institute Singapore (NCIS) - Centre Grant
Grant Reference no. : NMRC/CG/012/2013

This research / project is supported by the National University Cancer Institute Singapore (NCIS) - Centre Grant
Grant Reference no. : CGAug16M005

This research / project is supported by the Saw Swee Hock School of Public Health - Breast Cancer Prevention Program
Grant Reference no. : N.A

This research / project is supported by the National University Singapore (NUS) - Asian Breast Cancer Research Fund
Grant Reference no. : N.A

This research / project is supported by the National Medical Research Council - Clinician Scientist Award (SI Category)
Grant Reference no. : NMRC/CSA-SI/0015/2017

For overseas funding information, please refer to https://doi.org/10.1038/s41431-021-00987-7

https://oar.a-star.edu.sg/communities-collections/articles/18165

1018-4813
1476-5438

Genome Institute of Singapore

https://doi.org/10.1038/s41431-021-00987-7