Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations
- Jonathan 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-Rodriguez6,
- Mathew Garnett1,
- Clara Montagut5,
- Francesco Iorio2 and
- Ultan McDermott1,7
- 1 Wellcome Trust Sanger Institute;
- 2 EBI, Hinxton, UK;
- 3 FIMIM and Medical Oncology Department, Hospital del Mar, Barcelona;
- 4 Laboratorio Internacional de Investigación sobre el Genoma Humano;
- 5 FIMIM and Medical Oncology Department, Hospital del Mar, Barcelona, Spain;
- 6 WTH Aachen University Hospital, Aachen, Germany
- ↵* Corresponding author; email: um1{at}sanger.ac.uk
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 re-sensitize 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 have developed 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.
- Received July 28, 2016.
- Accepted February 7, 2017.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International license), as described at http://creativecommons.org/licenses/by/4.0/.
