Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
Baxter, J.S. ; Augustinsson, Annelie LU ; Olsson, Håkan LU
and Fletcher, O.
(2021)
In American Journal of Human Genetics
108(7).
p.1190-1203
- 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... (More)
- 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). © 2021 The Authors (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/a678bca8-9c60-4f2d-b241-08fb6933bd00
- author
- Baxter, J.S.
; Augustinsson, Annelie
LU
; Olsson, Håkan
LU
and Fletcher, O.
- author collaboration
- organization
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- breast cancer risk, functional annotation, risk locus, deoxyribonuclease I, transcription factor, Article, binding affinity, breast cancer, cancer risk, chromosome 2q, chromosome chromosome 2q35, computer model, controlled study, CRISPR Cas system, enhancer region, estrogen receptor positive breast cancer, gene deletion, gene expression, gene function, gene locus, gene mapping, genetic analysis, human, human cell, IGFBP5 gene, in vitro study, molecular genetics, odds ratio, regulatory sequence, reporter gene, risk reduction, tumor suppressor gene
- in
- American Journal of Human Genetics
- volume
- 108
- issue
- 7
- pages
- 14 pages
- publisher
- Cell Press
- external identifiers
-
- scopus:85111090849
- pmid:34146516
- ISSN
- 0002-9297
- DOI
- 10.1016/j.ajhg.2021.05.013
- language
- English
- LU publication?
- yes
- id
- a678bca8-9c60-4f2d-b241-08fb6933bd00
- date added to LUP
- 2021-12-28 12:09:54
- date last changed
- 2022-04-27 07:00:45
@article{a678bca8-9c60-4f2d-b241-08fb6933bd00,
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). © 2021 The Authors}},
author = {{Baxter, J.S. and Augustinsson, Annelie and Olsson, Håkan and Fletcher, O.}},
issn = {{0002-9297}},
keywords = {{breast cancer risk; functional annotation; risk locus; deoxyribonuclease I; transcription factor; Article; binding affinity; breast cancer; cancer risk; chromosome 2q; chromosome chromosome 2q35; computer model; controlled study; CRISPR Cas system; enhancer region; estrogen receptor positive breast cancer; gene deletion; gene expression; gene function; gene locus; gene mapping; genetic analysis; human; human cell; IGFBP5 gene; in vitro study; molecular genetics; odds ratio; regulatory sequence; reporter gene; risk reduction; tumor suppressor gene}},
language = {{eng}},
number = {{7}},
pages = {{1190--1203}},
publisher = {{Cell Press}},
series = {{American Journal of Human Genetics}},
title = {{Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element}},
url = {{http://dx.doi.org/10.1016/j.ajhg.2021.05.013}},
doi = {{10.1016/j.ajhg.2021.05.013}},
volume = {{108}},
year = {{2021}},
}