Forskning
Udskriv Udskriv
Switch language
Bispebjerg Hospital - en del af Københavns Universitetshospital
Udgivet

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

Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

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, J-Y, 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 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., ... NBCS Collaborators (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

CBE

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 J-Y, 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. 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

MLA

Vancouver

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. / 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{14143963ea4447f9a7734bc1d9d6812c,
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 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",
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 Ji-Yeob Choi 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}",
note = "Copyright {\textcopyright} 2021 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2021",
month = jul,
day = "1",
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

N1 - Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2021/7/1

Y1 - 2021/7/1

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 Neoplasms/genetics

KW - CRISPR-Cas Systems

KW - Cell Line

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 2

KW - Female

KW - Genetic Association Studies

KW - Genetic Variation

KW - Humans

KW - Insulin-Like Growth Factor Binding Protein 5/genetics

KW - Molecular Sequence Annotation

KW - Promoter Regions, Genetic

KW - Risk Factors

KW - Sequence Deletion

UR - http://www.scopus.com/inward/record.url?scp=85111090849&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2021.05.013

DO - 10.1016/j.ajhg.2021.05.013

M3 - Journal article

C2 - 34146516

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: 67448124