Toward an integrated map of genetic interactions in cancer cells

Molecular Systems Biology
Benedikt RauscherMichael Boutros

Abstract

Cancer genomes often harbor hundreds of molecular aberrations. Such genetic variants can be drivers or passengers of tumorigenesis and create vulnerabilities for potential therapeutic exploitation. To identify genotype-dependent vulnerabilities, forward genetic screens in different genetic backgrounds have been conducted. We devised MINGLE, a computational framework to integrate CRISPR/Cas9 screens originating from different libraries building on approaches pioneered for genetic network discovery in model organisms. We applied this method to integrate and analyze data from 85 CRISPR/Cas9 screens in human cancer cells combining functional data with information on genetic variants to explore more than 2.1 million gene-background relationships. In addition to known dependencies, we identified new genotype-specific vulnerabilities of cancer cells. Experimental validation of predicted vulnerabilities identified GANAB and PRKCSH as new positive regulators of Wnt/β-catenin signaling. By clustering genes with similar genetic interaction profiles, we drew the largest genetic network in cancer cells to date. Our scalable approach highlights how diverse genetic screens can be integrated to systematically build informative maps of genetic ...Continue Reading

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Citations

Feb 16, 2019·PLoS Genetics·José I Rojas EcheniqueMichael M Desai
Dec 24, 2018·Molecular Systems Biology·Evan A BoyleWilliam J Greenleaf
Jul 7, 2020·Molecular Systems Biology·Emanuel GonçalvesMathew J Garnett
May 15, 2019·Annual Review of Genomics and Human Genetics·Júlia DomingoBen Lehner
Apr 26, 2019·The CRISPR Journal·Matthew C CanverLuca Pinello
Oct 10, 2018·Genome Biology·Timothy P DaleyLei S Qi
Oct 20, 2020·Molecular Systems Biology·Sumana SharmaEvangelia Petsalaki
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Apr 17, 2021·Nature Genetics·Michael WainbergAnshul Kundaje
Oct 22, 2020·Cell Reports·Yingwei HuUNKNOWN Clinical Proteomic Tumor Analysis Consortium
May 22, 2021·Molecular Systems Biology·Mahfuzur RahmanChad L Myers
Jun 4, 2021·Nature Communications·Kemal AvicanMaria Fällman
May 25, 2021·Computational and Structural Biotechnology Journal·Desh Deepak SinghDharmendra Kumar Yadav

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Methods Mentioned

BETA
gene knockout
gene knockouts
ubiquitination
glycosylation
transfection
Hybrid
Assay

Software Mentioned

Bayesian Analysis of Gene Essentiality ( BAGEL
ConsensusPathDB
COSMIC
R package “ lme4
GenomeCRISPR
pheatmap
R package “ sfsmisc
Bioconductor
R
SAFE

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