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Toward an integrated map of genetic interactions in cancer cells
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 backgroun...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820685/ https://www.ncbi.nlm.nih.gov/pubmed/29467179 http://dx.doi.org/10.15252/msb.20177656 |
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author | Rauscher, Benedikt Heigwer, Florian Henkel, Luisa Hielscher, Thomas Voloshanenko, Oksana Boutros, Michael |
author_facet | Rauscher, Benedikt Heigwer, Florian Henkel, Luisa Hielscher, Thomas Voloshanenko, Oksana Boutros, Michael |
author_sort | Rauscher, Benedikt |
collection | PubMed |
description | 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 interactions in cancer, which can grow dynamically as more data are included. |
format | Online Article Text |
id | pubmed-5820685 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-58206852018-02-26 Toward an integrated map of genetic interactions in cancer cells Rauscher, Benedikt Heigwer, Florian Henkel, Luisa Hielscher, Thomas Voloshanenko, Oksana Boutros, Michael Mol Syst Biol Articles 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 interactions in cancer, which can grow dynamically as more data are included. John Wiley and Sons Inc. 2018-02-21 /pmc/articles/PMC5820685/ /pubmed/29467179 http://dx.doi.org/10.15252/msb.20177656 Text en © 2018 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles Rauscher, Benedikt Heigwer, Florian Henkel, Luisa Hielscher, Thomas Voloshanenko, Oksana Boutros, Michael Toward an integrated map of genetic interactions in cancer cells |
title | Toward an integrated map of genetic interactions in cancer cells |
title_full | Toward an integrated map of genetic interactions in cancer cells |
title_fullStr | Toward an integrated map of genetic interactions in cancer cells |
title_full_unstemmed | Toward an integrated map of genetic interactions in cancer cells |
title_short | Toward an integrated map of genetic interactions in cancer cells |
title_sort | toward an integrated map of genetic interactions in cancer cells |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820685/ https://www.ncbi.nlm.nih.gov/pubmed/29467179 http://dx.doi.org/10.15252/msb.20177656 |
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