CRISPR screens identify gene targets at breast cancer risk loci

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. PowellGeorgia Chenevix-Trench, Joseph Rosenbluh

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background: Genome-wide association studies (GWAS) have identified > 200 loci associated with breast cancer risk. The majority of candidate causal variants are in non-coding 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.

Original languageEnglish (US)
Article number59
JournalGenome biology
Volume24
Issue number1
DOIs
StatePublished - Dec 2023

Keywords

  • Breast cancer risk
  • Functional phenotypic screens
  • Post GWAS
  • Target discovery

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

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