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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kConFab Investigators , ABCTB Investigators , Baxter , J S & Nevanlinna , H 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 , vol. 108 , no. 7 , pp. 1190-1203 . https://doi.org/10.1016/j.ajhg.2021.05.013

Title: Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
Author: kConFab Investigators; ABCTB Investigators; Baxter, Joseph S.; Nevanlinna, Heli
Contributor organization: HUS Gynecology and Obstetrics
Department of Obstetrics and Gynecology
Biosciences
Date: 2021-07-01
Language: eng
Number of pages: 14
Belongs to series: American Journal of Human Genetics
ISSN: 0002-9297
DOI: https://doi.org/10.1016/j.ajhg.2021.05.013
URI: http://hdl.handle.net/10138/340316
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)).
Subject: SUSCEPTIBILITY LOCI
WIDE ASSOCIATION
IDENTIFICATION
TRANSCRIPTION
11Q13
RNAS
3122 Cancers
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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