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

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.

• Authors: 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 Stone, Marjanka K Schmidt, Annegien Broeks, Laura J Van't Veer, Frans B Hogervorst, Peter A Fasching, Lothar Haeberle, Arif B Ekici, Matthias W Beckmann, Lorna Gibson, Zoe Aitken, Helen Warren, Elinor Sawyer, Ian 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 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 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 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 Van Den 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 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, GENICA Network, kConFab Investigators, Australian Ovarian Cancer Study Group
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 10 Pg. 2966-84 (May 15 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 25652398 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
• Copyright: © The Author 2015. Published by Oxford University Press.

Chemical References

• ESR1 protein, human
• Estrogen Receptor alpha
• FOXA1 protein, human
• GATA3 Transcription Factor
• GATA3 protein, human
• Hepatocyte Nuclear Factor 3-alpha
• KLF4 protein, human
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors

Topics

• Adult
• Aged
• Asian People (genetics)
• Breast Neoplasms (genetics)
• Chromosome Mapping
• Chromosomes, Human, Pair 9
• Enhancer Elements, Genetic
• Estrogen Receptor alpha (genetics)
• Female
• GATA3 Transcription Factor (genetics)
• Genetic Association Studies
• Genetic Loci
• Genetic Predisposition to Disease
• Hepatocyte Nuclear Factor 3-alpha (genetics)
• Humans
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors (genetics)
• Middle Aged
• Polymorphism, Single Nucleotide
• Risk
• White People (genetics)