| Literature DB >> 27402876 |
Asaf Wyszynski1, Chi-Chen Hong2, Kristin Lam3, Kyriaki Michailidou4, Christian Lytle5, Song Yao2, Yali Zhang2, Manjeet K Bolla4, Qin Wang4, Joe Dennis4, John L Hopper6, Melissa C Southey7, Marjanka K Schmidt8, Annegien Broeks9, Kenneth Muir10,11, Artitaya Lophatananon12, Peter A Fasching13,14, Matthias W Beckmann13, Julian Peto15, Isabel Dos-Santos-Silva15, Elinor J Sawyer16, Ian Tomlinson9, Barbara Burwinkel12,17, Frederik Marme12,18, Pascal Guénel19,20, Thérèse Truong19,20, Stig E Bojesen21,22, Børge G Nordestgaard21,22, Anna González-Neira23, Javier Benitez24,25, Susan L Neuhausen26, Hermann Brenner27,28, Aida Karina Dieffenbach27,28, Alfons Meindl29, Rita K Schmutzler30,31,32,33, Hiltrud Brauch34,35, Heli Nevanlinna36, Sofia Khan36, Keitaro Matsuo37, Hidemi Ito38, Thilo Dörk39, Natalia V Bogdanova40, Annika Lindblom41, Sara Margolin42, Arto Mannermaa43,44,45, Veli-Matti Kosma43,44,45, Anna H Wu46, David Van Den Berg46, Diether Lambrechts47,48, Hans Wildiers49, Jenny Chang-Claude50,51, Anja Rudolph50, Paolo Radice52, Paolo Peterlongo53, Fergus J Couch54, Janet E Olson55, Graham G Giles56,6, Roger L Milne56,6, Christopher A Haiman46, Brian E Henderson46, Martine Dumont57, Soo Hwang Teo58,59, Tien Y Wong60, Vessela Kristensen61,62,63, Wei Zheng64, Jirong Long64, Robert Winqvist65, Katri Pylkäs65, Irene L Andrulis66,67, Julia A Knight68,69, Peter Devilee70, Caroline Seynaeve71, Montserrat García-Closas72,73, Jonine Figueroa74, Daniel Klevebring75, Kamila Czene75, Maartje J Hooning76, Ans M W van den Ouweland77, Hatef Darabi75, Xiao-Ou Shu64, Yu-Tang Gao78, Angela Cox79, William Blot64,80, Lisa B Signorello81, Mitul Shah82, Daehee Kang83,84,85, Ji-Yeob Choi84,85, Mikael Hartman86,87, Hui Miao86, Ute Hamann88, Anna Jakubowska89, Jan Lubinski89, Suleeporn Sangrajrang90, James McKay91, Amanda E Toland92, Drakoulis Yannoukakos93, Chen-Yang Shen94,95,96, Pei-Ei Wu94,95, Anthony Swerdlow72,97, Nick Orr98, Jacques Simard57, Paul D P Pharoah4,82, Alison M Dunning82, Georgia Chenevix-Trench99, Per Hall75, Elisa Bandera100, Chris Amos1, Christine Ambrosone2, Douglas F Easton101,102, Michael D Cole103.
Abstract
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.Entities:
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Year: 2016 PMID： 27402876 PMCID： PMC5216618 DOI： 10.1093/hmg/ddw223
Source DB: PubMed Journal: Hum Mol Genet ISSN： 0964-6906 Impact factor: 6.150