Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

Nick Orr, Frank Dudbridge, Nicola Dryden, Sarah Maguire, Daniela Novo, Eleni Perrakis, Nichola Johnson, Maya Ghoussaini, John L. Hopper, Melissa C. Southey, Carmel Apicella, Jennifer L Stone, Marjanka K. Schmidt, Annegien Broeks, Laura J. Van't Veer, Frans B. Hogervorst, Peter A. Fasching, Lothar Haeberle, Arif B Ekici, Matthias W. BeckmannLorna Gibson, Zoe Aitken, Helen Warren, Elinor J Sawyer, Ian P Tomlinson, Michael J. Kerin, Nicola Miller, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Chistof Sohn, Pascal Guénel, Thérèse Truong, Emilie Cordina-Duverger, Marie Sanchez, Stig E Bojesen, Børge G. Nordestgaard, Sune F Nielsen, Henrik Flyger, Javier Benitez, Maria Pilar Zamora, Jose Ignacio Arias Perez, Primitiva Menéndez, Hoda Anton-Culver, Susan L Neuhausen, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Ute Hamann, Hiltrud Brauch, Christina Justenhoven, Thomas Brüning, Yon-Dschun Ko, Heli Nevanlinna, Kristiina Aittomäki, Carl Blomqvist, Sofia Khan, Natalia Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Georgia Chenevix-Trench, Jonathan Beesley, Diether Lambrechts, Matthieu Moisse, Guiseppe Floris, Benoit Beuselinck, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernard Peissel, Valeria Pensotti, Fergus J Couch, Janet E Olson, Seth Slettedahl, Celine M Vachon, Graham G. Giles, Roger L Milne, Catriona McLean, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S. Goldberg, France Labrèche, Martine Dumont, Vessela Kristensen, Grethe Grenaker Alnæs, Silje Nord, Anne-Lise Borresen-Dale, Wei Zheng, Sandra Deming-Halverson, Martha Shrubsole, Jirong Long, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L Andrulis, Julia A Knight, Gord Glendon, Sandrine Tchatchou, Peter Devilee, Robertus A.E.M. Tollenaar, Caroline M. Seynaeve, Christi J. Van Asperen, Montserrat Garcia-Closas, Jonine D Figueroa, Stephen J Chanock, Jolanta Lissowska, Kamila Czene, Hatef Darabi, Mikael Eriksson, Daniel Klevebring, Maartje J Hooning, Antoinette Hollestelle, Carolien H.M. Van Deurzen, Mieke Kriege, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Angela Cox, Simon S Cross, Malcolm W R Reed, Paul D P Pharoah, Alison M Dunning, Mitul Shah, Barbara J. Perkins, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Alan Ashworth, Anthony J Swerdlow, Michael Jones, Minouk J. Schoemaker, Alfons Meindl, Rita K. Schmutzler, Curtis Olswold, Susan Slager, Amanda E. Toland, Drakoulis Yannoukakos, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Keitaro Matsuo, Hidema Ito, Hiroji Iwata, Junko Ishiguro, Anna H Wu, Chiu-Chen Tseng, David Berg, Daniel O Stram, Soo-Hwang Teo, Cheng Har Yip, Peter Kang, Mohammad Kamran Ikram, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Hui Cai, Daehee Kang, Ji Yeob Choi, Sue K. Park, Dong-Young Noh, Mikael Hartman, Hui Miao, Wei Yen Lim, Soo Chin Lee, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Pei-Ei Wu, Ming-Feng Hou, Jyh-Cherng Yu, Chen-Yang Shen, William Blot, Qiuyin Cai, Lisa B. Signorello, Craig Luccarini, Caroline Bayes, Shahana Ahmed, Mel J. Maranian, Catherine S. Healey, Anna González-Neira, Guillermo Pita, M. Rosario Alonso, Nuria Álvarez, Daniel Herrero, Daniel C. Tessier, Daniel Vincent, Francois Bacot, David J. Hunter, Sara Lindstrom, Joe Dennis, Kyriaki Michailidou, Manjeet K. Bolla, Douglas F Easton, Isabel Dos Santos Silva, Olivia Fletcher, Julian Peto, Australian Ovarian Cancer Study Group (AOCS), The GENICA Network

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29 Citations (Scopus)

Abstract

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10-25). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ~14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10-09) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10-11). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10-05). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.

Original languageEnglish
Pages (from-to)2966-2984
Number of pages19
JournalHuman Molecular Genetics
Volume24
Issue number10
DOIs
Publication statusPublished - 15 May 2015
Externally publishedYes

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