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

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Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element. / 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.; 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.; Flyger, Henrik; NBCS Collaborators; kConFab Investigators; ABCTB Investigators.

I: American Journal of Human Genetics, Bind 108, Nr. 7, 2021, s. 1190-1203.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt

Harvard

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, Flyger, H, NBCS Collaborators, kConFab Investigators & 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', American Journal of Human Genetics, bind 108, nr. 7, s. 1190-1203. https://doi.org/10.1016/j.ajhg.2021.05.013

APA

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., ... 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. American Journal of Human Genetics, 108(7), 1190-1203. https://doi.org/10.1016/j.ajhg.2021.05.013

Vancouver

Baxter JS, Johnson N, Tomczyk K, Gillespie A, Maguire S, Brough R o.a. Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element. American Journal of Human Genetics. 2021;108(7):1190-1203. https://doi.org/10.1016/j.ajhg.2021.05.013

Author

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. ; 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. ; Flyger, Henrik ; NBCS Collaborators ; kConFab Investigators ; ABCTB Investigators. / Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element. I: American Journal of Human Genetics. 2021 ; Bind 108, Nr. 7. s. 1190-1203.

Bibtex

@article{8f0fabb103554e28a85f772d194f8488,

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).",

keywords = "breast cancer risk, functional annotation, risk locus",

author = "Baxter, {Joseph S.} and Nichola Johnson and Katarzyna Tomczyk and Andrea Gillespie and Sarah Maguire and Rachel Brough and Laura Fachal and Kyriaki Michailidou and Bolla, {Manjeet K.} and Qin Wang and Joe Dennis and Ahearn, {Thomas U.} and Andrulis, {Irene L.} and Hoda Anton-Culver and Antonenkova, {Natalia N.} and Volker Arndt and Aronson, {Kristan J.} and Annelie Augustinsson and Heiko Becher and Beckmann, {Matthias W.} and Sabine Behrens and Javier Benitez and Marina Bermisheva and Bogdanova, {Natalia V.} and Bojesen, {Stig E.} and Hermann Brenner and Brucker, {Sara Y.} and Qiuyin Cai and Daniele Campa and Federico Canzian and Castelao, {Jose E.} and Chan, {Tsun L.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Georgia Chenevix-Trench and Choi, {Ji Yeob} and Clarke, {Christine L.} and Sarah Colonna and Conroy, {Don M.} and Couch, {Fergus J.} and Angela Cox and Cross, {Simon S.} and Kamila Czene and Daly, {Mary B.} and Peter Devilee and Thilo D{\"o}rk and Laure Dossus and Miriam Dwek and Eccles, {Diana M.} and Henrik Flyger and {NBCS Collaborators} and {kConFab Investigators} and {ABCTB Investigators}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

doi = "10.1016/j.ajhg.2021.05.013",

language = "English",

volume = "108",

pages = "1190--1203",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "7",

}

RIS

TY - JOUR

T1 - Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

AU - Baxter, Joseph S.

AU - Johnson, Nichola

AU - Tomczyk, Katarzyna

AU - Gillespie, Andrea

AU - Maguire, Sarah

AU - Brough, Rachel

AU - Fachal, Laura

AU - Michailidou, Kyriaki

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Dennis, Joe

AU - Ahearn, Thomas U.

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia N.

AU - Arndt, Volker

AU - Aronson, Kristan J.

AU - Augustinsson, Annelie

AU - Becher, Heiko

AU - Beckmann, Matthias W.

AU - Behrens, Sabine

AU - Benitez, Javier

AU - Bermisheva, Marina

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E.

AU - Brenner, Hermann

AU - Brucker, Sara Y.

AU - Cai, Qiuyin

AU - Campa, Daniele

AU - Canzian, Federico

AU - Castelao, Jose E.

AU - Chan, Tsun L.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Chenevix-Trench, Georgia

AU - Choi, Ji Yeob

AU - Clarke, Christine L.

AU - Colonna, Sarah

AU - Conroy, Don M.

AU - Couch, Fergus J.

AU - Cox, Angela

AU - Cross, Simon S.

AU - Czene, Kamila

AU - Daly, Mary B.

AU - Devilee, Peter

AU - Dörk, Thilo

AU - Dossus, Laure

AU - Dwek, Miriam

AU - Eccles, Diana M.

AU - Flyger, Henrik

AU - NBCS Collaborators

AU - kConFab Investigators

AU - ABCTB Investigators

PY - 2021

Y1 - 2021

N2 - 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).

AB - 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).

KW - breast cancer risk

KW - functional annotation

KW - risk locus

U2 - 10.1016/j.ajhg.2021.05.013

DO - 10.1016/j.ajhg.2021.05.013

M3 - Journal article

C2 - 34146516

AN - SCOPUS:85111090849

VL - 108

SP - 1190

EP - 1203

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 7

ER -

ID: 276331075

Institut for Klinisk Medicin