Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

M Dunning 1, Alison; Kyriaki Michailidou, 2; B Kuchenbaecker 2, Karoline; Deborah Thompson, 2; D French 3, Juliet; Jonathan Beesley, 3; S Healey 1, Catherine; Siddhartha Kar, 1; A Pooley 2, Karen; 4 5, Elena Lopez-Knowles; Ed Dicks, 1; Daniel Barrowdale, 2; A Sinnott-Armstrong 6, Nicholas; C Sallari 7, Richard; M Hillman 3, Kristine; Susanne Kaufmann, 3; Haran Sivakumaran, 3; Mahdi Moradi Marjaneh, 3; S Lee 3, Jason; Margaret Hills, 5; 4 5, Monika Jarosz; 4 5, Suzie Drury; Sander Canisius, 8; K Bolla 2, Manjeet; Joe Dennis, 2; Qin Wang, 2; L Hopper 9, John; Melissa, C Southey 10; Annegien Broeks, 8; K Schmidt 8, Marjanka; Artitaya Lophatananon 11,; Kenneth Muir 11 12,; Matthias, W Beckmann 13; Peter, A Fasching 13 14; Isabel Dos-Santos-Silva 15,; Julian Peto 15,; Elinor, J Sawyer 16; Ian Tomlinson 17 18,; Barbara Burwinkel 19 20,; Frederik Marme 21 22,; Pascal Guénel 23 24,; Thérèse Truong 23 24,; Stig, E Bojesen 25 26 27; Henrik Flyger 28,; Anna González-Neira 29,; Jose I, A Perez 30; Hoda Anton-Culver 31,; Lee Eunjung 32,; Volker Arndt 33,; Hermann Brenner 33 34,; Alfons Meindl 35,; Rita, K Schmutzler 36 37 38; Hiltrud Brauch 34 39 40,; Ute Hamann 41,; Kristiina Aittomäki 42,; Carl Blomqvist 43,; Hidemi Ito 44,; Keitaro Matsuo 45,; Natasha Bogdanova 46,; Thilo Dörk 47,; Annika Lindblom 48,; Sara Margolin 49,; Veli-Matti Kosma 50 51 52,; Arto Mannermaa 50 51 52,; Chiu-Chen Tseng 32,; Anna, H Wu 32; Diether Lambrechts 53 54,; Hans Wildiers 55,; Jenny Chang-Claude 56 57,; Anja Rudolph 56,; Paolo Peterlongo 58,; Paolo Radice 59,; Janet, E Olson 60; Graham G Giles, 9 61; Roger L Milne, 9 61; Christopher, A Haiman 32; Brian, E Henderson 32; Mark, S Goldberg 62 63; Soo, H Teo 64 65; Cheng Har Yip 65,; Silje Nord 66,; Anne-Lise Borresen-Dale 66 67,; Vessela Kristensen 66 67 68,; Jirong Long 69,; Wei Zheng 69,; Katri Pylkäs 70 71,; Robert Winqvist 70 71,; Irene, L Andrulis 72 73; Julia, A Knight 74 75; Peter Devilee 76 77,; Caroline Seynaeve 78,; Jonine Figueroa 79,; Mark, E Sherman 79; Kamila Czene 80,; Hatef Darabi 80,; Antoinette Hollestelle 78,; Ans M, W Van Den Ouweland 81; Keith Humphreys 80,; Yu-Tang Gao 82,; Xiao-Ou Shu 69,; Angela Cox 83,; Simon, S Cross 84; William Blot 69 85,; Qiuyin Cai 69,; Maya Ghoussaini, 1; J Perkins 1, Barbara; Mitul Shah, 1; Ji-Yeob Choi 86 87,; Daehee Kang 86 87 88,; Soo Chin Lee 89 90,; Mikael Hartman 91 92,; Maria Kabisch 41,; Diana Torres 41 93,; Anna Jakubowska 94,; Jan Lubinski 94,; Paul Brennan 95,; Suleeporn Sangrajrang 96,; Christine, B Ambrosone 97; Amanda, E Toland 98; Chen-Yang Shen 99 100,; Pei-Ei Wu 100,; Nick Orr 101,; Anthony Swerdlow 102 103,; Lesley Mcguffog, 2; Sue Healey, 3; Andrew Lee, 2; Miroslav Kapuscinski 104,; Esther, M John 105; Mary Beth Terry 106,; Mary, B Daly 107; David, E Goldgar 108; Saundra, S Buys 109; Ramunas Janavicius 110,; Laima Tihomirova 111,; Nadine Tung 112,; Cecilia, M Dorfling 113; Elizabeth, J Van Rensburg 113; Susan, L Neuhausen 114; Bent Ejlertsen 115,; Thomas V, O Hansen 116; Ana Osorio 117 118,; Javier Benitez 117 118 119,; Rachel Rando 120,; Jeffrey, N Weitzel 121; Bernardo Bonanni 122,; Bernard Peissel 123,; Siranoush Manoukian 123,; Papi, Laura; Laura Ottini 125,; Irene Konstantopoulou 126,; Paraskevi Apostolou 126,; Judy Garber 127,; Muhammad Usman Rashid 41 128,; Debra Frost, 2; Embrace,; Louise Izatt 129,; Steve Ellis, 2; Andrew, K Godwin 130; Norbert Arnold 131,; Dieter Niederacher 132,; Kerstin Rhiem 133,; Nadja Bogdanova-Markov 134,; Charlotte Sagne 135,; Dominique Stoppa-Lyonnet 136 137,; Francesca Damiola 135,; Gemo Study Collaborators,; Olga, M Sinilnikova 135 138; Sylvie Mazoyer 135,; Claudine Isaacs 139,; Kathleen B, M Claes 140; Kim De Leeneer 140,; Miguel De La Hoya 141,; Trinidad Caldes 141,; Heli Nevanlinna 142,; Sofia Khan 142,; Arjen, R Mensenkamp 143; Hebon,; Maartje, J Hooning 144; Matti, A Rookus 145; Ava Kwong 146 147,; Edith Olah 148,; Orland Diez 149,; Joan Brunet 150,; Miquel Angel Pujana 151,; Jacek Gronwald 94,; Tomasz Huzarski 94,; Rosa, B Barkardottir 152; Rachel Laframboise 153,; Penny Soucy 154,; Marco Montagna 155,; Simona Agata 155,; Manuel, R Teixeira 156 157; Investigators, Kconfab; Sue Kyung Park 86 87 88,; Noralane Lindor 60,; Fergus, J Couch 60 158; Marc Tischkowitz 159,; Lenka Foretova 160,; Joseph Vijai 161,; Kenneth Offit 161,; Christian, F Singer 162; Christine Rappaport 162,; Catherine, M Phelan 163; Mark, H Greene 164; Phuong, L Mai 164; Gad Rennert 165 166,; Evgeny, N Imyanitov 167; Peter, J Hulick 168; Kelly-Anne Phillips 169,; Marion Piedmonte 170,; Anna Marie Mulligan 171 172,; Gord Glendon 72,; Anders Bojesen 173,; Mads Thomassen 174,; Maria, A Caligo 175; Sook-Yee Yoon 64 176,; Eitan Friedman 177,; Yael Laitman 177,; Ake Borg 178,; Anna Von Wachenfeldt 49,; Hans Ehrencrona 179 180,; Johanna Rantala 181,; Olufunmilayo, I Olopade 182; Patricia, A Ganz 183; Robert, L Nussbaum 184; Simon, A Gayther 32; Katherine, L Nathanson 185; Susan, M Domchek 185; Banu, K Arun 186; Gillian Mitchell 187 188,; Beth, Y Karlan 189; Jenny Lester 189,; Gertraud Maskarinec 190,; Christy Woolcott 191,; Christopher Scott 60,; Jennifer Stone 192,; Carmel Apicella, 9; Rulla Tamimi 193 194 195,; Robert Luben 196,; Kay-Tee Khaw 196,; Åslaug Helland 66,; Vilde Haakensen 66,; 4 5, Mitch Dowsett; D P Pharoah 1 2, Paul; Jacques Simard 154,; Per Hall 80,; Montserrat García-Closas 101 102,; Celine Vachon 60,; Georgia Chenevix-Trench, 3; C Antoniou 2, Antonis; F Easton 1 2, Douglas; L Edwards 3, Stacey

doi:10.1038/ng.3521

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170 / Alison M Dunning 1, K.M.2., Louise Izatt 129, S.E.2., Olga M Sinilnikova 135 138, S.M.1., Maartje J Hooning 144, M.A.R.1., Sue Kyung Park 86 87 88, N.L.6.. - In: NATURE GENETICS. - ISSN 1061-4036. - STAMPA. - 48:(2016), pp. 374-386. [10.1038/ng.3521]