Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations
- Jonathan S. Brammeld1,
- Mia Petljak1,
- Inigo Martincorena1,
- Steven P. Williams1,
- Luz Garcia Alonso2,
- Alba Dalmases3,
- Beatriz Bellosillo3,
- Carla Daniela Robles-Espinoza4,
- Stacey Price1,
- Syd Barthorpe1,
- Patrick Tarpey1,
- Constantine Alifrangis1,
- Graham Bignell1,
- Joana Vidal5,
- Jamie Young1,
- Lucy Stebbings1,
- Kathryn Beal1,
- Michael R. Stratton1,
- Julio Saez-Rodriguez2,6,
- Mathew Garnett1,
- Clara Montagut5,
- Francesco Iorio2,7 and
- Ultan McDermott1,7
- 1Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom;
- 2European Molecular Biology Laboratory – European Bioinformatics Institute, Cambridge CB10 1SA, United Kingdom;
- 3Pathology Department, Hospital del Mar, 08003 Barcelona, Spain;
- 4Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Campus Juriquilla, Santiago de Querétaro 76230, Mexico;
- 5Cancer Research Program, FIMIM and Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain;
- 6RWTH Aachen University Hospital, 52062 Aachen, Germany
- Corresponding authors: um1{at}sanger.ac.uk, iorio{at}ebi.ac.uk
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↵7 Co-senior authors
Abstract
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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.213546.116.
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Freely available online through the Genome Research Open Access option.
- Received July 28, 2016.
- Accepted February 7, 2017.
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/.
