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

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

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

Daniel R Barnes 1, Matti A Rookus 2, Lesley McGuffog 3, Goska Leslie 3, Thea M Mooij 2, Joe Dennis 3, Nasim Mavaddat 3, Julian Adlard 4, Munaza Ahmed 5, Kristiina Aittomäki 6, Nadine Andrieu 7 8 9 10, Irene L Andrulis 11 12, Norbert Arnold 13 14, Banu K Arun 15, Jacopo Azzollini 16, Judith Balmaña 17 18, Rosa B Barkardottir 19 20, Daniel Barrowdale 3, Javier Benitez 21 22, Pascaline Berthet 23, Katarzyna Białkowska 24, Amie M Blanco 25, Marinus J Blok 26, Bernardo Bonanni 27, Susanne E Boonen 28, Åke Borg 29, Aniko Bozsik 30, Angela R Bradbury 31, Paul Brennan 32, Carole Brewer 33, Joan Brunet 34, Saundra S Buys 35, Trinidad Caldés 36, Maria A Caligo 37, Ian Campbell 38 39, Lise Lotte Christensen 40, Wendy K Chung 41, Kathleen B M Claes 42, Chrystelle Colas 43, GEMO Study Collaborators; EMBRACE Collaborators; Marie-Agnès Collonge-Rame 44, Jackie Cook 45, Mary B Daly 46, Rosemarie Davidson 47, Miguel de la Hoya 36, Robin de Putter 42, Capucine Delnatte 48, Peter Devilee 49 50, Orland Diez 51 52, Yuan Chun Ding 53, Susan M Domchek 54, Cecilia M Dorfling 55, Martine Dumont 56, Ros Eeles 57, Bent Ejlertsen 58, Christoph Engel 59, D Gareth Evans 60 61, Laurence Faivre 62 63, Lenka Foretova 64, Florentia Fostira 65, Michael Friedlander 66, Eitan Friedman 67 68, Debra Frost 3, Patricia A Ganz 69, Judy Garber 70, Andrea Gehrig 71, Anne-Marie Gerdes 72, Paul Gesta 73, Sophie Giraud 74, Gord Glendon 11, Andrew K Godwin 75, David E Goldgar 76, Anna González-Neira 22, Mark H Greene 77, Daphne Gschwantler-Kaulich 78, Eric Hahnen 79 80, Ute Hamann 81, Helen Hanson 82, Julia Hentschel 83, Frans B L Hogervorst 84, Maartje J Hooning 85, Judit Horvath 86, Chunling Hu 87, Peter J Hulick 88 89, Evgeny N Imyanitov 90, kConFab Investigators; HEBON Investigators; GENEPSO Investigators; Claudine Isaacs 91, Louise Izatt 92, Angel Izquierdo 34, Anna Jakubowska 24 93, Paul A James 39 94, Ramunas Janavicius 95 96, Esther M John 97, Vijai Joseph 98, Beth Y Karlan 99 100, Karin Kast 101, Marco Koudijs 102, Torben A Kruse 103, Ava Kwong 104 105 106, Yael Laitman 67, Christine Lasset 107 108, Conxi Lazaro 34, Jenny Lester 99 100, Fabienne Lesueur 7 8 9 10, Annelie Liljegren 109, Jennifer T Loud 77, Jan Lubiński 24, Phuong L Mai 110, Siranoush Manoukian 16, Véronique Mari 111, Noura Mebirouk 7 8 9 10, Hanne E J Meijers-Heijboer 112, Alfons Meindl 113, Arjen R Mensenkamp 114, Austin Miller 115, Marco Montagna 116, Emmanuelle Mouret-Fourme 43, Semanti Mukherjee 117, Anna Marie Mulligan 118 119, Katherine L Nathanson 54, Susan L Neuhausen 53, Heli Nevanlinna 120, Dieter Niederacher 121, Finn Cilius Nielsen 122, Liene Nikitina-Zake 123, Catherine Noguès 124, Edith Olah 30, Olufunmilayo I Olopade 125, Kai-Ren Ong 126, Aoife O'Shaughnessy-Kirwan 127, Ana Osorio 21 22, Claus-Eric Ott 128, Laura Papi 129, Sue K Park 130 131 132, Michael T Parsons 133, Inge Sokilde Pedersen 134 135 136, Bernard Peissel 16, Ana Peixoto 137, Paolo Peterlongo 138, Georg Pfeiler 139, Kelly-Anne Phillips 38 39 140 141, Karolina Prajzendanc 24, Miquel Angel Pujana 142, Paolo Radice 143, Juliane Ramser 144, Susan J Ramus 145 146 147, Johanna Rantala 148, Gad Rennert 149, Harvey A Risch 150, Mark Robson 117, Karina Rønlund 151, Ritu Salani 152, Hélène Schuster 153 154 155, Leigha Senter 156, Payal D Shah 31, Priyanka Sharma 157, Lucy E Side 158, Christian F Singer 139, Thomas P Slavin 159, Penny Soucy 56, Melissa C Southey 160 161 162, Amanda B Spurdle 133, Doris Steinemann 163, Zoe Steinsnyder 117, Dominique Stoppa-Lyonnet 43 164 165, Christian Sutter 166, Yen Yen Tan 78, Manuel R Teixeira 137 167, Soo Hwang Teo 168 169, Darcy L Thull 170, Marc Tischkowitz 171 172, Silvia Tognazzo 116, Amanda E Toland 173, Alison H Trainer 94 174, Nadine Tung 175, Klaartje van Engelen 176, Elizabeth J van Rensburg 55, Ana Vega 21 177 178, Jeroen Vierstraete 42, Gabriel Wagner 139, Lisa Walker 179, Shan Wang-Gohrke 180, Barbara Wappenschmidt 79 80, Jeffrey N Weitzel 159, Siddhartha Yadav 181, Xin Yang 3, Drakoulis Yannoukakos 65, Dario Zimbalatti 16, Kenneth Offit 98 117, Mads Thomassen 103, Fergus J Couch 87, Rita K Schmutzler 79 80 182, Jacques Simard 56, Douglas F Easton 3 183, Georgia Chenevix-Trench 133, Antonis C Antoniou 3, Consortium of Investigators of Modifiers of BRCA and BRCA2

Collaborators, Affiliations 

• PMID: 32665703
 
• DOI: 10.1038/s41436-020-0862-x

Abstract

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: 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.

Keywords: BRCA1/2; PRS; breast cancer; genetics; ovarian cancer.

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