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Type: Journal article
Title: CRISPR screens identify gene targets at breast cancer risk loci
Author: Tuano, N.K.
Beesley, J.
Manning, M.
Shi, W.
Perlaza-Jimenez, L.
Malaver-Ortega, L.F.
Paynter, J.M.
Black, D.
Civitarese, A.
McCue, K.
Hatzipantelis, A.
Hillman, K.
Kaufmann, S.
Sivakumaran, H.
Polo, J.M.
Reddel, R.R.
Band, V.
French, J.D.
Edwards, S.L.
Powell, D.R.
et al.
Citation: Genome Biology, 2023; 24(1):59-59
Publisher: Springer Science and Business Media LLC
Issue Date: 2023
ISSN: 1474-7596
Statement of
Natasha K. Tuano, Jonathan Beesley, Murray Manning, Wei Shi, Laura Perlaza, Jimenez, Luis F. Malaver, Ortega, Jacob M. Paynter, Debra Black, Andrew Civitarese, Karen McCue, Aaron Hatzipantelis, Kristine Hillman, Susanne Kaufmann, Haran Sivakumaran, Jose M. Polo, Roger R. Reddel, Vimla Band, Juliet D. French, Stacey L. Edwards, David R. Powell, Georgia Chenevix, Trench, and Joseph Rosenbluh
Abstract: Background: Genome-wide association studies (GWAS) have identified > 200 loci associated with breast cancer risk. The majority of candidate causal variants are in noncoding regions and likely modulate cancer risk by regulating gene expression. However, pinpointing the exact target of the association, and identifying the phenotype it mediates, is a major challenge in the interpretation and translation of GWAS. Results: Here, we show that pooled CRISPR screens are highly effective at identifying GWAS target genes and defining the cancer phenotypes they mediate. Following CRISPR mediated gene activation or suppression, we measure proliferation in 2D, 3D, and in immune-deficient mice, as well as the effect on DNA repair. We perform 60 CRISPR screens and identify 20 genes predicted with high confidence to be GWAS targets that promote cancer by driving proliferation or modulating the DNA damage response in breast cells. We validate the regulation of a subset of these genes by breast cancer risk variants. Conclusions: We demonstrate that phenotypic CRISPR screens can accurately pinpoint the gene target of a risk locus. In addition to defining gene targets of risk loci associated with increased breast cancer risk, we provide a platform for identifying gene targets and phenotypes mediated by risk variants.
Keywords: Post GWAS; Breast cancer risk; Functional phenotypic screens; Target discovery
Rights: © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
DOI: 10.1186/s13059-023-02898-w
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Appears in Collections:Medical Sciences publications

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