Détail du document
Identifiant
doi:10.1186/s13059-023-02898-w...
Auteur
Tuano, Natasha K. Beesley, Jonathan Manning, Murray Shi, Wei Perlaza-Jimenez, Laura Malaver-Ortega, Luis F. Paynter, Jacob M. Black, Debra Civitarese, Andrew McCue, Karen Hatzipantelis, Aaron Hillman, Kristine Kaufmann, Susanne Sivakumaran, Haran Polo, Jose M. Reddel, Roger R. Band, Vimla French, Juliet D. Edwards, Stacey L. Powell, David R. Chenevix-Trench, Georgia Rosenbluh, JosephLangue
enEditeur
BioMed Central
Catégorie
Life Sciences
Année
2023
Date de référencement
05/04/2023
Mots clés
post gwas breast cancer risk functional phenotypic screens target discovery loci variants genes identifying risk breast screens gwas targets cancerRésumé
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.
Tuano, Natasha K.,Beesley, Jonathan,Manning, Murray,Shi, Wei,Perlaza-Jimenez, Laura,Malaver-Ortega, Luis F.,Paynter, Jacob M.,Black, Debra,Civitarese, Andrew,McCue, Karen,Hatzipantelis, Aaron,Hillman, Kristine,Kaufmann, Susanne,Sivakumaran, Haran,Polo, Jose M.,Reddel, Roger R.,Band, Vimla,French, Juliet D.,Edwards, Stacey L.,Powell, David R.,Chenevix-Trench, Georgia,Rosenbluh, Joseph, 2023, CRISPR screens identify gene targets at breast cancer risk loci, BioMed Central
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