Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55–0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10−19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10−15 − 5.6 × 10−17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.
An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression
Asaf Wyszynski, Chi-Chen Hong, Kristin Lam, Kyriaki Michailidou, Christian Lytle, Song Yao, Yali Zhang, Manjeet K. Bolla, Qin Wang, Joe Dennis, John L. Hopper, Melissa C. Southey, Marjanka K. Schmidt, Annegien Broeks, Kenneth Muir, Artitaya Lophatananon, Peter A. Fasching, Matthias W. Beckmann, Julian Peto, Isabel dos-Santos-Silva, Elinor J. Sawyer, Ian Tomlinson, Barbara Burwinkel, Frederik Marme, Pascal Guénel, Thérèse Truong, Stig E. Bojesen, Børge G. Nordestgaard, Anna González-Neira, Javier Benitez, Susan L. Neuhausen, Hermann Brenner, Aida Karina Dieffenbach, Alfons Meindl, Rita K. Schmutzler, Hiltrud Brauch, The GENICA Network, Heli Nevanlinna, Sofia Khan, Keitaro Matsuo, Hidemi Ito, Thilo Dörk, Natalia V. Bogdanova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Veli-Matti Kosma, kConFab Investigators, Australian Ovarian Cancer Study Group, Anna H. Wu, David Van Den Berg, Diether Lambrechts, Hans Wildiers, Jenny Chang-Claude, Anja Rudolph, Paolo Radice, Paolo Peterlongo, Fergus J. Couch, Janet E. Olson, Graham G. Giles, Roger L. Milne, Christopher A. Haiman, Brian E. Henderson, Martine Dumont, Soo Hwang Teo, Tien Y. Wong, Vessela Kristensen, Wei Zheng, Jirong Long, Robert Winqvist, Katri Pylkäs, Irene L. Andrulis, Julia A. Knight, Peter Devilee, Caroline Seynaeve, Montserrat García-Closas, Jonine Figueroa, Daniel Klevebring, Kamila Czene, Maartje J. Hooning, Ans M.W. van den Ouweland, Hatef Darabi, Xiao-Ou Shu, Yu-Tang Gao, Angela Cox, William Blot, Lisa B. Signorello, Mitul Shah, Daehee Kang, Ji-Yeob Choi, Mikael Hartman, Hui Miao, Ute Hamann, Anna Jakubowska, Jan Lubinski, Suleeporn Sangrajrang, James McKay, Amanda E. Toland, Drakoulis Yannoukakos, Chen-Yang Shen, Pei-Ei Wu, Anthony Swerdlow, Nick Orr, Jacques Simard, Paul D.P. Pharoah, Alison M. Dunning, Georgia Chenevix-Trench, Per Hall, Elisa Bandera, Chris Amos, Christine Ambrosone, Douglas F. Easton, Michael D. Cole; An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression. Hum Mol Genet 2016; 25 (17): 3863-3876. doi: 10.1093/hmg/ddw223
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