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

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; NBCS Collaborators; Colonna, S; Conroy, DM; Couch, FJ; Cox, A; Cross, SS; Czene, K; Daly, MB; Devilee, P; Dork, T; Dossus, L; Dwek, M; Eccles, DM; Ekici, AB; Eliassen, AH; Engel, C; Fasching, PA; Figueroa, J; Flyger, H; Gago-Dominguez, M; Gao, C; Garcia-Closas, M; Garcia-Saenz, JA; Ghoussaini, M; Giles, GG; Goldberg, MS; Gonzalez-Neira, A; Guenel, P; Gundert, 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; kConFab Investigators; ABCTB Investigators; 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; Lubinski, 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&#39;Brien, KM; Offit, K; Olson, JE; Olsson, H; Park, SK; Park-Simon, TW; Patel, AV; Peterlongo, P; Peto, J; Plaseska-Karanfilska, D; Presneau, N; Pylkas, K; Rack, B; Rennert, G; Romero, A; Ruebner, M; Rudiger, 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

Author(s): 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; NBCS Collaborators; Colonna, S; Conroy, DM; Couch, FJ; Cox, A; Cross, SS; Czene, K; Daly, MB; Devilee, P; Dork, T; Dossus, L; Dwek, M; Eccles, DM; Ekici, AB; Eliassen, AH; Engel, C; Fasching, PA; Figueroa, J; Flyger, H; Gago-Dominguez, M; Gao, C; Garcia-Closas, M; Garcia-Saenz, JA; Ghoussaini, M; Giles, GG; Goldberg, MS; Gonzalez-Neira, A; Guenel, P; Gundert, 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; kConFab Investigators; ABCTB Investigators; 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; Lubinski, 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; Pylkas, K; Rack, B; Rennert, G; Romero, A; Ruebner, M; Rudiger, 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;
Details: Publication Year 2021-07-01,Volume 108,Issue #7,Page 1190-1203
Journal Title: American Journal of Human Genetics
Publication Type: Research article
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 x 10(-31)).
Keywords: Breast Neoplasms/genetics; CRISPR-Cas Systems; Cell Line; Chromosome Mapping; Chromosomes, Human, Pair 2; Female; Genetic Association Studies; Genetic Variation; Humans; Insulin-Like Growth Factor Binding Protein 5/*genetics; *Molecular Sequence Annotation; *Promoter Regions, Genetic; Risk Factors; Sequence Deletion; breast cancer risk; functional annotation; risk locus
Department(s): Laboratory Research
PubMed ID: 34146516
Publisher's Version: https://doi.org/10.1016/j.ajhg.2021.05.013
Open Access at Publisher's Site: https://doi.org/10.1016/j.ajhg.2021.05.013
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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