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

Daniel Barnes 1 Matti Rookus 2 Lesley Mcguffog 1 Goska Leslie 1 Thea Mooij 2 Joe Dennis 1 Nasim Mavaddat 1 Julian Adlard 3 Munaza Ahmed 4 Kristiina Aittomäki 5 Nadine Andrieu 6, 7, 8, 9 Irene Andrulis 10, 11 Norbert Arnold 12 Banu Arun 13 Jacopo Azzollini 14 Judith Balmaña 15, 16 Rosa Barkardottir 17, 18 Daniel Barrowdale 1 Javier Benitez 19, 20 Pascaline Berthet 21 Katarzyna Białkowska 22 Amie Blanco 23 Marinus Blok 24 Bernardo Bonanni 25 Susanne Boonen 26 Åke Borg 27 Aniko Bozsik 28 Angela Bradbury 29 Paul Brennan 30 Carole Brewer 31 Joan Brunet 32 Saundra Buys 33 Trinidad Caldés 34 Maria Caligo 35 Ian Campbell 36, 37 Lise Lotte Christensen 38 Wendy Chung 39 Kathleen Claes 40 Chrystelle Colas 7 Marie-Agnès Collonge-Rame 41 Jackie Cook 42 Mary Daly 43 Rosemarie Davidson 44 Miguel de la Hoya 34 Robin de Putter 40 Capucine Delnatte 45 Peter Devilee 46 Orland Diez 15, 16 Yuan Chun Ding 47 Susan Domchek 48 Cecilia Dorfling 49 Martine Dumont 50 Ros Eeles 51 Bent Ejlertsen 52 Christoph Engel 53 D Gareth Evans 54, 55 Laurence Faivre 56, 57 Lenka Foretova 58 Florentia Fostira 59 Michael Friedlander 60 Eitan Friedman 61, 62 Debra Frost 1 Patricia Ganz 63 Judy Garber 64 Andrea Gehrig 65 Anne-Marie Gerdes 66 Paul Gesta 67 Sophie Giraud 68 Gord Glendon 10 Andrew Godwin 69 David Goldgar 33 Anna González-Neira 20 Mark Greene 70 Daphne Gschwantler-Kaulich 71 Eric Hahnen 72 Ute Hamann 73 Helen Hanson 74 Julia Hentschel 75 Frans Hogervorst 2 Maartje Hooning 76 Judit Horvath 77 Chunling Hu 78 Peter Hulick 79, 80 Evgeny Imyanitov 81 Claudine Isaacs 82 Louise Izatt 83 Angel Izquierdo 32 Anna Jakubowska 22 Paul James 37, 84 Ramunas Janavicius 85, 86 Esther John 87 Vijai Joseph 88 Beth Karlan 23, 89 Karin Kast 90 Marco Koudijs 91 Torben Kruse 92 Ava Kwong 93, 94, 95 Yael Laitman 61 Christine Lasset 96, 97 Conxi Lazaro 32 Jenny Lester 98, 89 Fabienne Lesueur 6, 7, 9, 99 Annelie Liljegren 100 Jennifer Loud 70 Jan Lubiński 22 Phuong Mai 101 Siranoush Manoukian 14 Véronique Mari 102 Noura Mebirouk 6, 7, 99, 9 Hanne Meijers-Heijboer 103 Alfons Meindl 104 Arjen Mensenkamp 105 Austin Miller 106 Marco Montagna 107 Emmanuelle Mouret-Fourme 7 Semanti Mukherjee 88 Anna Marie Mulligan 108, 109 Katherine Nathanson 110 Susan Neuhausen 47 Heli Nevanlinna 5 Dieter Niederacher 111 Finn Cilius Nielsen 52 Liene Nikitina-Zake 112 Catherine Nogues 113, 114 Edith Olah 28 Olufunmilayo Olopade 115 Kai-Ren Ong 116 Aoife O'Shaughnessy-Kirwan 117 Ana Osorio 19, 20 Claus-Eric Ott 118 Laura Papi 119 Sue Park 120, 121 Michael Parsons 122 Inge Sokilde Pedersen 123 Bernard Peissel 124 Ana Peixoto 125 Paolo Peterlongo 126 Georg Pfeiler 71 Kelly-Anne Phillips 127, 37 Karolina Prajzendanc 22 Miquel Angel Pujana 128 Paolo Radice 124 Juliane Ramser 129 Susan Ramus 130, 131 Johanna Rantala 100 Gad Rennert 132 Harvey Risch 133 Mark Robson 88 Karina Rønlund 134 Ritu Salani 135 Hélène Schuster 136, 137, 138 Leigha Senter 135 Payal Shah 48 Priyanka Sharma 139 Lucy Side 140 Christian Singer 71 Thomas Slavin 141 Penny Soucy 50 Melissa Southey 142, 37, 143 Amanda Spurdle 122 Doris Steinemann 144 Zoe Steinsnyder 88 Dominique Stoppa-Lyonnet 7, 145, 146 Christian Sutter 147 Yen Yen Tan 71 Manuel Teixeira 125, 148 Soo Hwang Teo 149, 150 Darcy Thull 101 Marc Tischkowitz 151, 1 Silvia Tognazzo 107 Amanda Toland 135 Alison Trainer 127, 37 Nadine Tung 152 Klaartje van Engelen 103 Elizabeth van Rensburg 49 Ana Vega 19, 153, 154 Jeroen Vierstraete 155 Gabriel Wagner 71 Lisa Walker 156 Shan Wang-Gohrke 157 Barbara Wappenschmidt 158 Jeffrey Weitzel 141 Siddhartha Yadav 159 Xin Yang 1 Drakoulis Yannoukakos 59 Dario Zimbalatti 124 Kenneth Offit 88 Mads Thomassen 92 Fergus Couch 159 Rita Schmutzler 158 Jacques Simard 50 Douglas Easton 1 Georgia Chenevix-Trench 122 Antonis Antoniou 1
Abstract : 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: 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. 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.
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Daniel Barnes, Matti Rookus, Lesley Mcguffog, Goska Leslie, Thea Mooij, et al.. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants. Genetics in Medicine, Nature Publishing Group, 2020, 22 (10), pp.1653-1666. ⟨10.1038/s41436-020-0862-x⟩. ⟨inserm-03193473⟩

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