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Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations

Drug resistance is an almost inevitable consequence of cancer therapy and ultimately proves fatal for the majority of patients. In many cases, this is the consequence of specific gene mutations that have the potential to be targeted to resensitize the tumor. The ability to uniformly saturate the gen...

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Autores principales: Brammeld, Jonathan S., Petljak, Mia, Martincorena, Inigo, Williams, Steven P., Alonso, Luz Garcia, Dalmases, Alba, Bellosillo, Beatriz, Robles-Espinoza, Carla Daniela, Price, Stacey, Barthorpe, Syd, Tarpey, Patrick, Alifrangis, Constantine, Bignell, Graham, Vidal, Joana, Young, Jamie, Stebbings, Lucy, Beal, Kathryn, Stratton, Michael R., Saez-Rodriguez, Julio, Garnett, Mathew, Montagut, Clara, Iorio, Francesco, McDermott, Ultan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378179/
https://www.ncbi.nlm.nih.gov/pubmed/28179366
http://dx.doi.org/10.1101/gr.213546.116
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author Brammeld, Jonathan S.
Petljak, Mia
Martincorena, Inigo
Williams, Steven P.
Alonso, Luz Garcia
Dalmases, Alba
Bellosillo, Beatriz
Robles-Espinoza, Carla Daniela
Price, Stacey
Barthorpe, Syd
Tarpey, Patrick
Alifrangis, Constantine
Bignell, Graham
Vidal, Joana
Young, Jamie
Stebbings, Lucy
Beal, Kathryn
Stratton, Michael R.
Saez-Rodriguez, Julio
Garnett, Mathew
Montagut, Clara
Iorio, Francesco
McDermott, Ultan
author_facet Brammeld, Jonathan S.
Petljak, Mia
Martincorena, Inigo
Williams, Steven P.
Alonso, Luz Garcia
Dalmases, Alba
Bellosillo, Beatriz
Robles-Espinoza, Carla Daniela
Price, Stacey
Barthorpe, Syd
Tarpey, Patrick
Alifrangis, Constantine
Bignell, Graham
Vidal, Joana
Young, Jamie
Stebbings, Lucy
Beal, Kathryn
Stratton, Michael R.
Saez-Rodriguez, Julio
Garnett, Mathew
Montagut, Clara
Iorio, Francesco
McDermott, Ultan
author_sort Brammeld, Jonathan S.
collection PubMed
description Drug resistance is an almost inevitable consequence of cancer therapy and ultimately proves fatal for the majority of patients. In many cases, this is the consequence of specific gene mutations that have the potential to be targeted to resensitize the tumor. The ability to uniformly saturate the genome with point mutations without chromosome or nucleotide sequence context bias would open the door to identify all putative drug resistance mutations in cancer models. Here, we describe such a method for elucidating drug resistance mechanisms using genome-wide chemical mutagenesis allied to next-generation sequencing. We show that chemically mutagenizing the genome of cancer cells dramatically increases the number of drug-resistant clones and allows the detection of both known and novel drug resistance mutations. We used an efficient computational process that allows for the rapid identification of involved pathways and druggable targets. Such a priori knowledge would greatly empower serial monitoring strategies for drug resistance in the clinic as well as the development of trials for drug-resistant patients.
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spelling pubmed-53781792017-04-12 Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations Brammeld, Jonathan S. Petljak, Mia Martincorena, Inigo Williams, Steven P. Alonso, Luz Garcia Dalmases, Alba Bellosillo, Beatriz Robles-Espinoza, Carla Daniela Price, Stacey Barthorpe, Syd Tarpey, Patrick Alifrangis, Constantine Bignell, Graham Vidal, Joana Young, Jamie Stebbings, Lucy Beal, Kathryn Stratton, Michael R. Saez-Rodriguez, Julio Garnett, Mathew Montagut, Clara Iorio, Francesco McDermott, Ultan Genome Res Method Drug resistance is an almost inevitable consequence of cancer therapy and ultimately proves fatal for the majority of patients. In many cases, this is the consequence of specific gene mutations that have the potential to be targeted to resensitize the tumor. The ability to uniformly saturate the genome with point mutations without chromosome or nucleotide sequence context bias would open the door to identify all putative drug resistance mutations in cancer models. Here, we describe such a method for elucidating drug resistance mechanisms using genome-wide chemical mutagenesis allied to next-generation sequencing. We show that chemically mutagenizing the genome of cancer cells dramatically increases the number of drug-resistant clones and allows the detection of both known and novel drug resistance mutations. We used an efficient computational process that allows for the rapid identification of involved pathways and druggable targets. Such a priori knowledge would greatly empower serial monitoring strategies for drug resistance in the clinic as well as the development of trials for drug-resistant patients. Cold Spring Harbor Laboratory Press 2017-04 /pmc/articles/PMC5378179/ /pubmed/28179366 http://dx.doi.org/10.1101/gr.213546.116 Text en © 2017 Brammeld et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
spellingShingle Method
Brammeld, Jonathan S.
Petljak, Mia
Martincorena, Inigo
Williams, Steven P.
Alonso, Luz Garcia
Dalmases, Alba
Bellosillo, Beatriz
Robles-Espinoza, Carla Daniela
Price, Stacey
Barthorpe, Syd
Tarpey, Patrick
Alifrangis, Constantine
Bignell, Graham
Vidal, Joana
Young, Jamie
Stebbings, Lucy
Beal, Kathryn
Stratton, Michael R.
Saez-Rodriguez, Julio
Garnett, Mathew
Montagut, Clara
Iorio, Francesco
McDermott, Ultan
Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations
title Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations
title_full Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations
title_fullStr Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations
title_full_unstemmed Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations
title_short Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations
title_sort genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations
topic Method
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378179/
https://www.ncbi.nlm.nih.gov/pubmed/28179366
http://dx.doi.org/10.1101/gr.213546.116
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