Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Authors: Daniel R. Barnes, Matti A. Rookus, Lesley McGuffog, Goska Leslie, Thea M. Mooij, Joe Dennis, Nasim Mavaddat, Julian Adlard, Munaza Ahmed, Kristiina Aittomäki, Nadine Andrieu, Irene L. Andrulis, Norbert Arnold, Banu Arun, Jacopo Azzollini, Judith Balmañà, Rósa B. Barkardóttir, Daniel Barrowdale, Javier Benı́tez, Pascaline Berthet, Katarzyna Białkowska, Amie Blanco, Marinus J. Blok, Bernardo Bonanni, Susanne E. Boonen, Åke Borg, Anikó Bozsik, Angela R. Bradbury, Paul Brennan, Carole Brewer, Joan Brunet, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Lise Lotte Christensen, Wendy K. Chung, Kathleen Claes, Chrystelle Colas, Pascaline Berthet, Chrystelle Colas, Marie‐Agnès Collonge‐Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret‐Fourme, Hélène Schuster, Dominique Stoppa‐Lyonnet, Julian Adlard, Munaza Ahmed, Antonis C. Antoniou, Daniel Barrowdale, Paul Brennan, Carole Brewer, Jackie Cook, Rosemarie Davidson, Douglas F. Easton, Rosalind A. Eeles, D. Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-Ren Ong, Lucy Side, Aoife O’Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Marie‐Agnès Collonge‐Rame, Jackie Cook, Mary B. Daly, Rosemarie Davidson, Miguel de la Hoya, Robin De Putter, Capucine Delnatte, Peter Devilee, Orland Dı́ez, Yuan Chun Ding, Susan M. Domchek, Cecilia M. Dorfling, Martine Dumont, Rosalind A. Eeles, Bent Ejlertsen, Christoph Engel, D. Gareth Evans, Laurence Faivre, Lenka Foretová, Florentia Fostira, Michael Friedländer, Eitan Friedman, Debra Frost, Patricia A. Ganz, Judy E. Garber, Andrea Gehrig, Anne‐Marie Gerdes, Paul Gesta, Sophie Giraud, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Anna González‐Neira, Mark H. Greene, Daphne Gschwantler‐Kaulich, Eric Hahnen, Ute Hamann, Helen Hanson, Julia Hentschel, Frans B.L. Hogervorst, Maartje J. Hooning, Judit Horváth, Chunling Hu, Peter J. Hulick, Evgeny N. Imyanitov, Georgia Chenevix‐Trench, Kelly‐Anne Phillips, Amanda B. Spurdle, Marinus J. Blok, Peter Devilee, Frans B.L. Hogervorst, Maartje J. Hooning, Marco J. Koudijs, Arjen R. Mensenkamp, Hanne Meijers‐Heijboer, Matti A. Rookus, Klaartje van Engelen, Nadine Andrieu, Catherine Noguès, Claudine Isaacs, Louise Izatt, Á. Izquierdo, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Joseph Vijai, Beth Y. Karlan, Karin Kast, Marco J. Koudijs, Torben A. Kruse, Ava Kwong, Yael Laitman, Christine Lasset, Conxi Lázaro, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Jennifer T. Loud, Jan Lubiński, Phuong L. Mai, Siranoush Manoukian, Véronique Mari, Noura Mebirouk, Hanne Meijers‐Heijboer, Alfons Meindl, Arjen R. Mensenkamp, Austin Miller, Marco Montagna, Emmanuelle Mouret‐Fourme, Semanti Mukherjee, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Dieter Niederacher, Finn Cilius Nielsen, Liene Ņikitina-Zaķe, Catherine Noguès, Edith Olah, Olufunmilayo I. Olopade, Kai-Ren Ong, Aoife O’Shaughnessy-Kirwan, Ana Osório, Claus‐Eric Ott, Laura Papi, Sue K. Park, Michael T. Parsons, Inge Søkilde Pedersen, Bernard Peissel, Ana Peixoto, Paolo Peterlongo, Georg Pfeiler, Kelly‐Anne Phillips, Karolina Prajzendanc, Miguel Ángel Pujana, Paolo Radice, Juliane Ramser, Susan J. Ramus, Johanna Rantala, Gad Rennert, Harvey A. Risch, Mark E. Robson, Karina Rønlund, Ritu Salani, Hélène Schuster, Leigha Senter, Payal D. Shah, Priyanka Sharma, Lucy Side, Christian F. Singer, Thomas P. Slavin, Penny Soucy, Melissa C. Southey, Amanda B. Spurdle, Doris Steinemann, Zoe Steinsnyder, Dominique Stoppa‐Lyonnet, Christian Sutter, Yen Y. Tan, Manuel R. Teixeira, Soo‐Hwang Teo, Darcy L. Thull, Marc Tischkowitz, Silvia Tognazzo, Amanda E. Toland, Alison H. Trainer, Nadine Tung, Klaartje van Engelen, Elizabeth J. van Rensburg, Ana Vega, Jeroen Vierstraete, Gabriel Wagner, Lisa Walker, Shan Wang‐Gohrke, Barbara Wappenschmidt, Jeffrey N. Weitzel, Siddhartha Yadav, Xin Yang, Drakoulis Yannoukakos, Dario Zimbalatti, Kenneth Offit, Mads Thomassen, Fergus J. Couch, Rita K. Schmutzler, Jacques Simard, Douglas F. Easton, Georgia Chenevix‐Trench, Antonis C. Antoniou - Genetics in Medicine 2020 cited by 145

PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: ) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.