Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element Journal Article
| Authors: | Baxter, J. S.; Johnson, N.; Tomczyk, K.; Gillespie, A.; Maguire, S.; Brough, R.; Fachal, L.; Michailidou, K.; Bolla, M. K.; Wang, Q.; Dennis, J.; Ahearn, T. U.; Andrulis, I. L.; Anton-Culver, H.; Antonenkova, N. N.; Arndt, V.; Aronson, K. J.; Augustinsson, A.; Becher, H.; Beckmann, M. W.; Behrens, S.; Benitez, J.; Bermisheva, M.; Bogdanova, N. V.; Bojesen, S. E.; Brenner, H.; Brucker, S. Y.; Cai, Q.; Campa, D.; Canzian, F.; Castelao, J. E.; Chan, T. L.; Chang-Claude, J.; Chanock, S. J.; Chenevix-Trench, G.; Choi, J. Y.; Clarke, C. L.; NBCS Collaborators; Colonna, S.; Conroy, D. M.; Couch, F. J.; Cox, A.; Cross, S. S.; Czene, K.; Daly, M. B.; Devilee, P.; Dörk, T.; Dossus, L.; Dwek, M.; Eccles, D. M.; Ekici, A. B.; Eliassen, A. H.; Engel, C.; Fasching, P. A.; Figueroa, J.; Flyger, H.; Gago-Dominguez, M.; Gao, C.; García-Closas, M.; García-Sáenz, J. A.; Ghoussaini, M.; Giles, G. G.; Goldberg, M. S.; González-Neira, A.; Guénel, P.; Gündert, M.; Haeberle, L.; Hahnen, E.; Haiman, C. A.; Hall, P.; Hamann, U.; Hartman, M.; Hatse, S.; Hauke, J.; Hollestelle, A.; Hoppe, R.; Hopper, J. L.; Hou, M. F.; kConFab Investigators; ABCTB Investigators; Ito, H.; Iwasaki, M.; Jager, A.; Jakubowska, A.; Janni, W.; John, E. M.; Joseph, V.; Jung, A.; Kaaks, R.; Kang, D.; Keeman, R.; Khusnutdinova, E.; Kim, S. W.; Kosma, V. M.; Kraft, P.; Kristensen, V. N.; Kubelka-Sabit, K.; Kurian, A. W.; Kwong, A.; Lacey, J. V.; Lambrechts, D.; Larson, N. L.; Larsson, S. C.; 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, R. L.; Mohd Taib, N. A.; Muir, K.; Muranen, T. A.; Murphy, R. A.; Nevanlinna, H.; O'Brien, K. M.; Offit, K.; Olson, J. E.; Olsson, H.; Park, S. K.; Park-Simon, T. W.; Patel, A. V.; Peterlongo, P.; Peto, J.; Plaseska-Karanfilska, D.; Presneau, N.; Pylkäs, K.; Rack, B.; Rennert, G.; Romero, A.; Ruebner, M.; Rüdiger, T.; Saloustros, E.; Sandler, D. P.; Sawyer, E. J.; Schmidt, M. K.; Schmutzler, R. K.; Schneeweiss, A.; Schoemaker, M. J.; Shah, M.; Shen, C. Y.; Shu, X. O.; Simard, J.; Southey, M. C.; Stone, J.; Surowy, H.; Swerdlow, A. J.; Tamimi, R. M.; Tapper, W. J.; Taylor, J. A.; Teo, S. H.; Teras, L. R.; Terry, M. B.; Toland, A. E.; Tomlinson, I.; Truong, T.; Tseng, C. C.; Untch, M.; Vachon, C. M.; van den Ouweland, A. M. W.; Wang, S. S.; Weinberg, C. R.; Wendt, C.; Winham, S. J.; Winqvist, R.; Wolk, A.; Wu, A. H.; Yamaji, T.; Zheng, W.; Ziogas, A.; Pharoah, P. D. P.; Dunning, A. M.; Easton, D. F.; Pettitt, S. J.; Lord, C. J.; Haider, S.; Orr, N.; Fletcher, O. |
| Article Title: | Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element |
| 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). © 2021 The Authors |
| Keywords: | controlled study; human cell; gene deletion; cancer risk; molecular genetics; binding affinity; genetic analysis; breast cancer; gene expression; gene locus; odds ratio; transcription factor; gene function; in vitro study; gene mapping; tumor suppressor gene; reporter gene; computer model; risk reduction; enhancer region; breast cancer risk; regulatory sequence; chromosome 2q; risk locus; deoxyribonuclease i; functional annotation; estrogen receptor positive breast cancer; human; article; crispr cas system; chromosome chromosome 2q35; igfbp5 gene |
| Journal Title: | American Journal of Human Genetics |
| Volume: | 108 |
| Issue: | 7 |
| ISSN: | 0002-9297 |
| Publisher: | Cell Press |
| Date Published: | 2021-07-01 |
| Start Page: | 1190 |
| End Page: | 1203 |
| Language: | English |
| DOI: | 10.1016/j.ajhg.2021.05.013 |
| PROVIDER: | scopus |
| PMCID: | PMC8322933 |
| PUBMED: | 34146516 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 September 2021 -- Source: Scopus |
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