RT Journal
A1 Brammeld, Jonathan S.
A1 Petljak, Mia
A1 Martincorena, Inigo
A1 Williams, Steven P.
A1 Alonso, Luz Garcia
A1 Dalmases, Alba
A1 Bellosillo, Beatriz
A1 Robles-Espinoza, Carla Daniela
A1 Price, Stacey
A1 Barthorpe, Syd
A1 Tarpey, Patrick
A1 Alifrangis, Constantine
A1 Bignell, Graham
A1 Vidal, Joana
A1 Young, Jamie
A1 Stebbings, Lucy
A1 Beal, Kathryn
A1 Stratton, Michael R.
A1 Saez-Rodriguez, Julio
A1 Garnett, Mathew
A1 Montagut, Clara
A1 Iorio, Francesco
A1 McDermott, Ultan
T1 Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations
JF Genome Research 
JO Genome Research 
YR 2017 
FD February 08 
DO 10.1101/gr.213546.116 
UL http://genome.cshlp.org/content/early/2017/03/15/gr.213546.116.abstract 
AB 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.