The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Nom de la revue
Genetics in Medicine
Inge M.M. Lakeman, Alexandra J. van den Broek, Juliën A.M. Vos, Daniel R. Barnes, Julian Adlard, Irene L. Andrulis, Adalgeir Arason, Norbert Arnold, Banu K. Arun, Judith Balmaña, Daniel Barrowdale, Javier Benitez, Ake Borg, Trinidad Caldés, Maria A. Caligo, Wendy K. Chung, Kathleen B.M. Claes, Emmanuelle Barouk-Simonet, Muriel Belotti, Pascaline Berthet, Yves-Jean Bignon, Valérie Bonadona, Brigitte Bressac-de Paillerets, Bruno Buecher, Sandrine Caputo, Olivier Caron, Laurent Castera, Virginie Caux-Moncoutier, Chrystelle Colas, Marie-Agnès Collonge-Rame, Isabelle Coupier, Antoine de Pauw, Capucine Delnatte, Camille Elan, Laurence Faivre, Sandra Fert Ferrer, Marion Gauthier-Villars, Paul Gesta, Sophie Giraud, Lisa Golmard, Claude Houdayer, Christine Lasset, Maïté Laurent, Dominique Leroux, Michel Longy, Véronique Mari, Sylvie Mazoyer, Noura Mebirouk, Isabelle Mortemousque, Fabienne Prieur, Pascal Pujol, Claire Saule, Helene Schuster, Nicolas Sevenet, Hagay Sobol, Johanna Sokolowska, Laurence Venat-Bouvet, Munaza Ahmed, Julian Barwell, Angela Brady, Paul Brennan, Carole Brewer, Jackie Cook, Rosemarie Davidson, Alan Donaldson, Alison M. Dunning, Jacqueline Eason, Diana M. Eccles, Helen Gregory, Helen Hanson, Patricia A. Harrington, Alex Henderson, Shirley Hodgson, M. John Kennedy, Fiona Lalloo, Clare Miller, Patrick J. Morrison, Kai-ren Ong, Aoife O’Shaughnessy-Kirwan, Jo Perkins, Mary E. Porteous, Mark T. Rogers, Lucy E. Side, Katie Snape, Lisa Walker, J. Margriet Collée, Fergus J. Couch, Mary B. Daly, Joe Dennis, Mallika Dhawan, Susan M. Domchek, Ros Eeles, Christoph Engel, D. Gareth Evans, Lidia Feliubadaló, Lenka Foretova, Eitan Friedman, Debra Frost, Patricia A. Ganz, Judy Garber, Simon A. Gayther, Anne-Marie Gerdes, Andrew K. Godwin, David E. Goldgar, Eric Hahnen, Christopher R. Hake, Ute Hamann, Frans B.L. Hogervorst, Maartje J. Hooning, John L. Hopper, Peter J. Hulick, Evgeny N. Imyanitov, Gord Glendon, Anna Marie Mulligan, Christi J. van Asperen, Cora M. Aalfs, Muriel A. Adank, Margreet G.E.M. Ausems, Marinus J. Blok, Encarna B. Gómez Garcia, Bernadette A.M. Heemskerk-Gerritsen, Antoinette Hollestelle, Agnes Jager, Linetta B. Koppert, Marco Koudijs, Mieke Kriege, Hanne E.J. Meijers-Heijboer, Arjen R. Mensenkamp, Thea M. Mooij, Jan C. Oosterwijk, Ans M.W. van den Ouweland, Frederieke H. van der Baan, Annemieke H. van der Hout, Lizet E. van der Kolk, Rob B. van der Luijt, Carolien H.M. van Deurzen, Helena C. van Doorn, Klaartje van Engelen, Liselotte P. van Hest, Theo A.M. van Os, Senno Verhoef, Maartje J. Vogel, Juul T. Wijnen, Jonathan Beesley, Stephen Fox, Helene Holland, Kelly-Anne Phillips, Amanda B. Spurdle, Claudine Isaacs, Louise Izatt, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Uffe Birk Jensen, Yue Jiao, Esther M. John, Vijai Joseph, Beth Y. Karlan, Carolien M. Kets, Irene Konstantopoulou, Ava Kwong, Clémentine Legrand, Goska Leslie, Fabienne Lesueur, Jennifer T. Loud, Jan Lubiński, Siranoush Manoukian, Lesley McGuffog, Austin Miller, Denise Molina Gomes, Marco Montagna, Emmanuelle Mouret-Fourme, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Joanne Ngeow Yuen Yie, Edith Olah, Olufunmilayo I. Olopade, Sue K. Park, Michael T. Parsons, Paolo Peterlongo, Marion Piedmonte, Paolo Radice, Johanna Rantala, Gad Rennert, Harvey A. Risch, Rita K. Schmutzler, Priyanka Sharma, Jacques Simard, Christian F. Singer, Zsofia Stadler, Dominique Stoppa-Lyonnet, Christian Sutter, Yen Yen Tan, Manuel R. Teixeira, Soo Hwang Teo, Alex Teulé, Mads Thomassen, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Nadine Tung, Elizabeth J. van Rensburg, Ana Vega, Barbara Wappenschmidt, Peter Devilee, Christi J. van Asperen, Jonine L. Bernstein, Kenneth Offit, Douglas F. Easton, Matti A. Rookus, Georgia Chenevix-Trench, Antonis C. Antoniou, Mark Robson, Marjanka K. Schmidt
Abstract

Abstract
Purpose
To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

Methods
We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk.

Results
For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.

Conclusion
The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.