Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations
Brammeld, Jonathan S. (Wellcome Trust Sanger Institute (Regne Unit))
Petljak, Mia (Wellcome Trust Sanger Institute (Regne Unit))
Martincorena, Inigo (Wellcome Trust Sanger Institute (Regne Unit))
Williams, Steven P. (Wellcome Trust Sanger Institute (Regne Unit))
García Alonso, Luz (European Molecular Biology Laboratory (Regne Unit))
Dalmases, Alba (Hospital del Mar (Barcelona, Catalunya))
Bellosillo Paricio, Beatriz (Hospital del Mar (Barcelona, Catalunya))
Robles-Espinoza, Carla Daniela (Universidad Nacional Autónoma de México)
Price, Stacey (Wellcome Trust Sanger Institute (Regne Unit))
Barthorpe, Syd (Wellcome Trust Sanger Institute (Regne Unit))
Tarpey, Patrick (Wellcome Trust Sanger Institute (Regne Unit))
Alifrangis, Constantine (Wellcome Trust Sanger Institute (Regne Unit))
Bignell, Graham (Wellcome Trust Sanger Institute (Regne Unit))
Vidal, Joana (Institut Hospital del Mar d'Investigacions Mèdiques)
Young, Jamie (Wellcome Trust Sanger Institute (Regne Unit))
Stebbings, Lucy (Wellcome Trust Sanger Institute (Regne Unit))
Beal, Kathryn (Wellcome Trust Sanger Institute (Regne Unit))
Stratton, Michael R. (Wellcome Trust Sanger Institute (Regne Unit))
Saez-Rodriguez, Julio (University Hospital Aachen (Alemanya))
Garnett, Mathew (Wellcome Trust Sanger Institute (Regne Unit))
Montagut, Clara (Institut Hospital del Mar d'Investigacions Mèdiques)
Iorio, Francesco (European Molecular Biology Laboratory (Regne Unit))
McDermott, Ultan (Wellcome Trust Sanger Institute (Regne Unit))
Universitat Autònoma de Barcelona

Data:	2017
Resum:	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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Genome research, Vol. 27 (april 2017) , p. 613-625, ISSN 1549-5469

DOI: 10.1101/gr.213546.116
PMID: 28179366

13 p, 1.8 MB

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