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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

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@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