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Baxter, J.S.; Johnson, N.; Tomczyk, K.; Gillespie, A.; Maguire, S.; Brough, R.; ... ; ABCTB Investigators (2021)

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

Article / Letter to editor
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...Show moreA 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 x 10(-31)).Show less
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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.Y.; 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.; Collaborators, N.; Colonna, S.; Conroy, D.M.; Couch, F.J.; Cox, A.; Cross, S.S.; Czene, K.; Daly, M.B.; Devilee, P.; Dork, 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.; Garcia-Closas, M.; Garcia-Saenz, J.A.; Ghoussaini, M.; Giles, G.G.; Goldberg, M.S.; Gonzalez-Neira, A.; Guenel, P.; Gundert, 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.; 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.; Marchand, L. le; Lejbkowicz, F.; Li, J.M.; Long, J.R.; Lophatananon, A.; LubiNski, J.; Mannermaa, A.; Manoochehri, M.; Manoukian, S.; Margolin, S.; Matsuo, K.; Mavroudis, D.; Mayes, R.; Menon, U.; Milne, R.L.; Taib, N.A.M.; 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.; Pylkas, K.; Rack, B.; Rennert, G.; Romero, A.; Ruebner, M.; Rudiger, 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.; Ouweland, A.M.W. van den; 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.; kConFab Investigators; ABCTB Investigators
Date
2021-07-01
Journal
American Journal of Human Genetics
Volume
108
Issue
7
Pages
1190 - 1203
DOI
doi:10.1016/j.ajhg.2021.05.013
Link
http://www.cell.com/article/S0002929721002184/pdf