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

Daniel R. Barnes, GEMO Study Collaborators, Matti A. Rookus, Lesley McGuffog, Goska Leslie, Thea M. Mooij, Joe Dennis, Nasim Mavaddat, Julian Adlard, Munaza Ahmed, Kristiina Aittomäki, Nadine Andrieu (+188 others)
2020 Genetics in Medicine  

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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. 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
more » ... BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar. 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.
doi:10.1038/s41436-020-0862-x pmid:32665703 pmcid:PMC7521995 fatcat:qg6jfftkuze4ddaniv3ce4iff4
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Daniel R. Barnes, GEMO Study Collaborators, 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 K. Arun, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel Barrowdale, Javier Benitez, Pascaline Berthet, Katarzyna Białkowska, Amie M. Blanco, Marinus J. Blok, Bernardo Bonanni, Susanne E. Boonen, Åke Borg, Aniko 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 B. M. Claes, Chrystelle Colas, Marie-Agnès Collonge-Rame, Jackie Cook, Mary B. Daly, Rosemarie Davidson, Miguel de la Hoya, Robin de Putter, Capucine Delnatte, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Cecilia M. Dorfling, Martine Dumont, Ros Eeles, Bent Ejlertsen, Christoph Engel, D. Gareth Evans, Laurence Faivre, Lenka Foretova, Florentia Fostira, Michael Friedlander, Eitan Friedman, Debra Frost, Patricia A. Ganz, Judy 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 Horvath, Chunling Hu, Peter J. Hulick, Evgeny N. Imyanitov, Claudine Isaacs, Louise Izatt, Angel Izquierdo, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Vijai Joseph, Beth Y. Karlan, Karin Kast, Marco Koudijs, Torben A. Kruse, Ava Kwong, Yael Laitman, Christine Lasset, Conxi Lazaro, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Jennifer T. Loud, Jan Lubiński, Phuong L. Mai, Siranoush Manoukian, Véronique Mari, Noura Mebirouk, Hanne E. J. 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 Nikitina-Zake, Catherine Noguès, Edith Olah, Olufunmilayo I. Olopade, Kai-ren Ong, Aoife O'Shaughnessy-Kirwan, Ana Osorio, Claus-Eric Ott, Laura Papi, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Bernard Peissel, Ana Peixoto, Paolo Peterlongo, Georg Pfeiler, Kelly-Anne Phillips, Karolina Prajzendanc, Miquel Angel Pujana, Paolo Radice, Juliane Ramser, Susan J. Ramus, Johanna Rantala, Gad Rennert, Harvey A. Risch, Mark Robson, Karina Rønlund, Ritu Salani, Hélène Schuster, Leigha Senter, Payal D. Shah, Priyanka Sharma, Lucy E. 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 Yen 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, EMBRACE Collaborators, kConFab Investigators, HEBON Investigators, GENEPSO Investigators, on behalf of the Consortium of Investigators of Modifiers of BRCA and BRCA2. "Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants." Genetics in Medicine 22.10 (2020) 1653-1666