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 Beckmann,
Sabine 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,
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,
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
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).