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Baxter JS , Johnson N , Tomczyk K , Gillespie A , Maguire S , Brough R , Fachal L , Michailidou K , Bolla MK , Wang Q , Dennis J , Ahearn TU , Andrulis IL , Anton-Culver H , Antonenkova NN , Arndt V , Aronson KJ , Augustinsson A , Becher H , Beckmann MW , Behrens S , Benitez J , Bermisheva M , Bogdanova NV , Bojesen SE , Brenner H , Brucker SY , Cai Q , Campa D , Canzian F , Castelao JE , Chan TL , Chang-Claude J , Chanock SJ , Chenevix-Trench G , Choi JY , Clarke CL , Colonna S , Conroy DM , Couch FJ , Cox A , Cross SS , Czene K , Daly MB , Devilee P , Dörk T , Dossus L , Dwek M , Eccles DM , Ekici AB , Eliassen AH , Engel C , Fasching PA , Figueroa J , Flyger H , Gago-Dominguez M , Gao C , García-Closas M , García-Sáenz JA , Ghoussaini M , Giles GG , Goldberg MS , González-Neira A , Guénel P , Gündert M , Haeberle L , Hahnen E , Haiman CA , Hall P , Hamann U , Hartman M , Hatse S , Hauke J , Hollestelle A , Hoppe R , Hopper JL , Hou MF , Ito H , Iwasaki M , Jager A , Jakubowska A , Janni W , John EM , Joseph V , Jung A , Kaaks R , Kang D , Keeman R , Khusnutdinova E , Kim SW , Kosma VM , Kraft P , Kristensen VN , Kubelka-Sabit K , Kurian AW , Kwong A , Lacey JV , Lambrechts D , Larson NL , Larsson SC , Le Marchand L , Lejbkowicz F , Li J , Long J , Lophatananon A , Lubiński J , Mannermaa A , Manoochehri M , Manoukian S , Margolin S , Matsuo K , Mavroudis D , Mayes R , Menon U , Milne RL , Mohd Taib NA , Muir K , Muranen TA , Murphy RA , Nevanlinna H , O'Brien KM , Offit K , Olson JE , Olsson H , Park SK , Park-Simon TW , Patel AV , Peterlongo P , Peto J , Plaseska-Karanfilska D , Presneau N , Pylkäs K , Rack B , Rennert G , Romero A , Ruebner M , Rüdiger T , Saloustros E , Sandler DP , Sawyer EJ , Schmidt MK , Schmutzler RK , Schneeweiss A , Schoemaker MJ , Shah M , Shen CY , Shu XO , Simard J , Southey MC , Stone J , Surowy H , Swerdlow AJ , Tamimi RM , Tapper WJ , Taylor JA , Teo SH , Teras LR , Terry MB , Toland AE , Tomlinson I , Truong T , Tseng CC , Untch M , Vachon CM , van den Ouweland AMW , Wang SS , Weinberg CR , Wendt C , Winham SJ , Winqvist R , Wolk A , Wu AH , Yamaji T , Zheng W , Ziogas A , Pharoah PDP , Dunning AM , Easton DF , Pettitt SJ , Lord CJ , Haider S , Orr N , Fletcher O
Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
Am J Hum Genet. 2021 Jul 1;108(7) :1190-1203
PMID: 34146516    PMCID: PMC8322933    URL: https://www.ncbi.nlm.nih.gov/pubmed/34146516
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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)).
Notes
1537-6605 Baxter, Joseph S Johnson, Nichola Tomczyk, Katarzyna Gillespie, Andrea Maguire, Sarah Brough, Rachel Fachal, Laura Michailidou, Kyriaki Bolla, Manjeet K Wang, Qin Dennis, Joe Ahearn, Thomas U Andrulis, Irene L Anton-Culver, Hoda Antonenkova, Natalia N Arndt, Volker Aronson, Kristan J Augustinsson, Annelie Becher, Heiko Beckmann, Matthias W Behrens, Sabine Benitez, Javier Bermisheva, Marina Bogdanova, Natalia V Bojesen, Stig E Brenner, Hermann Brucker, Sara Y Cai, Qiuyin Campa, Daniele Canzian, Federico Castelao, Jose E Chan, Tsun L Chang-Claude, Jenny Chanock, Stephen J Chenevix-Trench, Georgia Choi, Ji-Yeob Clarke, Christine L NBCS Collaborators Colonna, Sarah Conroy, Don M Couch, Fergus J Cox, Angela Cross, Simon S Czene, Kamila Daly, Mary B Devilee, Peter Dörk, Thilo Dossus, Laure Dwek, Miriam Eccles, Diana M Ekici, Arif B Eliassen, A Heather Engel, Christoph Fasching, Peter A Figueroa, Jonine Flyger, Henrik Gago-Dominguez, Manuela Gao, Chi García-Closas, Montserrat García-Sáenz, José A Ghoussaini, Maya Giles, Graham G Goldberg, Mark S González-Neira, Anna Guénel, Pascal Gündert, Melanie Haeberle, Lothar Hahnen, Eric Haiman, Christopher A Hall, Per Hamann, Ute Hartman, Mikael Hatse, Sigrid Hauke, Jan Hollestelle, Antoinette Hoppe, Reiner Hopper, John L Hou, Ming-Feng kConFab Investigators ABCTB Investigators Ito, Hidemi Iwasaki, Motoki Jager, Agnes Jakubowska, Anna Janni, Wolfgang John, Esther M Joseph, Vijai Jung, Audrey Kaaks, Rudolf Kang, Daehee Keeman, Renske Khusnutdinova, Elza Kim, Sung-Won Kosma, Veli-Matti Kraft, Peter Kristensen, Vessela N Kubelka-Sabit, Katerina Kurian, Allison W Kwong, Ava Lacey, James V Lambrechts, Diether Larson, Nicole L Larsson, Susanna C Le Marchand, Loic Lejbkowicz, Flavio Li, Jingmei Long, Jirong Lophatananon, Artitaya Lubiński, Jan Mannermaa, Arto Manoochehri, Mehdi Manoukian, Siranoush Margolin, Sara Matsuo, Keitaro Mavroudis, Dimitrios Mayes, Rebecca Menon, Usha Milne, Roger L Mohd Taib, Nur Aishah Muir, Kenneth Muranen, Taru A Murphy, Rachel A Nevanlinna, Heli O'Brien, Katie M Offit, Kenneth Olson, Janet E Olsson, Håkan Park, Sue K Park-Simon, Tjoung-Won Patel, Alpa V Peterlongo, Paolo Peto, Julian Plaseska-Karanfilska, Dijana Presneau, Nadege Pylkäs, Katri Rack, Brigitte Rennert, Gad Romero, Atocha Ruebner, Matthias Rüdiger, Thomas Saloustros, Emmanouil Sandler, Dale P Sawyer, Elinor J Schmidt, Marjanka K Schmutzler, Rita K Schneeweiss, Andreas Schoemaker, Minouk J Shah, Mitul Shen, Chen-Yang Shu, Xiao-Ou Simard, Jacques Southey, Melissa C Stone, Jennifer Surowy, Harald Swerdlow, Anthony J Tamimi, Rulla M Tapper, William J Taylor, Jack A Teo, Soo Hwang Teras, Lauren R Terry, Mary Beth Toland, Amanda E Tomlinson, Ian Truong, Thérèse Tseng, Chiu-Chen Untch, Michael Vachon, Celine M van den Ouweland, Ans M W Wang, Sophia S Weinberg, Clarice R Wendt, Camilla Winham, Stacey J Winqvist, Robert Wolk, Alicja Wu, Anna H Yamaji, Taiki Zheng, Wei Ziogas, Argyrios Pharoah, Paul D P Dunning, Alison M Easton, Douglas F Pettitt, Stephen J Lord, Christopher J Haider, Syed Orr, Nick Fletcher, Olivia Journal Article United States Am J Hum Genet. 2021 Jun 16:S0002-9297(21)00218-4. doi: 10.1016/j.ajhg.2021.05.013.