Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

Joseph S. Baxter, Nichola Johnson, Katarzyna Tomczyk, Andrea Gillespie, Sarah Maguire, Rachel Brough, Laura Fachal, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Annelie Augustinsson, Heiko Becher, Matthias W. BeckmannSabine Behrens, Javier Benitez, Marina Bermisheva, Natalia V. Bogdanova, Stig E. Bojesen, Hermann Brenner, Sara Y. Brucker, Qiuyin Cai, Daniele Campa, Federico Canzian, Jose E. Castelao, Tsun L. Chan, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, Ji Yeob Choi, Christine L. Clarke, Sarah Colonna, Don M. Conroy, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Laure Dossus, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Christoph Engel, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, Manuela Gago-Dominguez, Chi Gao, Montserrat García-Closas, José A. García-Sáenz, Maya Ghoussaini, Graham G. Giles, Mark S. Goldberg, Anna González-Neira, Pascal Guénel, Melanie Gündert, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Per Hall, Ute Hamann, Mikael Hartman, Sigrid Hatse, Jan Hauke, Antoinette Hollestelle, Reiner Hoppe, John L. Hopper, Ming Feng Hou, Hidemi Ito, Motoki Iwasaki, Agnes Jager, Anna Jakubowska, Wolfgang Janni, Esther M. John, Vijai Joseph, Audrey Jung, Rudolf Kaaks, Daehee Kang, Renske Keeman, Elza Khusnutdinova, Sung Won Kim, Veli Matti Kosma, Peter Kraft, Vessela N. Kristensen, Katerina Kubelka-Sabit, Allison W. Kurian, Ava Kwong, James V. Lacey, Diether Lambrechts, Nicole L. Larson, Susanna C. Larsson, Loic Le Marchand, Flavio Lejbkowicz, Jingmei Li, Jirong Long, Artitaya Lophatananon, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Keitaro Matsuo, Dimitrios Mavroudis, Rebecca Mayes, Usha Menon, Roger L. Milne, Nur Aishah Mohd Taib, Kenneth Muir, Taru A. Muranen, Rachel A. Murphy, Heli Nevanlinna, Katie M. O'Brien, Kenneth Offit, Janet E. Olson, Håkan Olsson, Sue K. Park, Tjoung Won Park-Simon, Alpa V. Patel, Paolo Peterlongo, Julian Peto, Dijana Plaseska-Karanfilska, Nadege Presneau, Katri Pylkäs, Brigitte Rack, Gad Rennert, Atocha Romero, Matthias Ruebner, Thomas Rüdiger, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Mitul Shah, Chen Yang Shen, Xiao Ou Shu, Jacques Simard, Melissa C. Southey, Jennifer Stone, Harald Surowy, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Soo Hwang Teo, Lauren R. Teras, Mary Beth Terry, Amanda E. Toland, Ian Tomlinson, Thérèse Truong, Chiu Chen Tseng, Michael Untch, Celine M. Vachon, Ans M.W. van den Ouweland, Sophia S. Wang, Clarice R. Weinberg, Camilla Wendt, Stacey J. Winham, Robert Winqvist, Alicja Wolk, Anna H. Wu, Taiki Yamaji, Wei Zheng, Argyrios Ziogas, Paul D.P. Pharoah, Alison M. Dunning, Douglas F. Easton, Stephen J. Pettitt, Christopher J. Lord, Syed Haider, Nick Orr, Olivia Fletcher, NBCS Collaborators, kConFab Investigators, ABCTB Investigators

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4 Citations (Scopus)

Abstract

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74–0.81, p = 3.1 × 10−31).

Original languageEnglish
Pages (from-to)1190-1203
Number of pages14
JournalAmerican Journal of Human Genetics
Volume108
Issue number7
DOIs
Publication statusPublished - Jul 2021

Keywords

  • breast cancer risk
  • functional annotation
  • risk locus

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